Jose Musacchio, M.D.

Why do qualia and the mind seem nonphysical?
Musacchio, JM
2005 DEC ;147(3):425-460, Synthese
In this article, I discuss several of the factors that jeopardize our understanding of the nature of qualitative experiences and the mind. I incorporate the view from neuroscience to clarify the naive view from the first person perspective. I suggest that the most misleading factor in the understanding the nature of the mind and conscious processes is the transparency of experiences and the imperceptibility of the neurobiological processes that realize them. Transparency reflects the biological advantages provided to organisms by avoiding the proliferation of superfluous sensing and the regress implied in sensing the sensors and analyzers ad infinitum. The downside of simplicity and the price for biological efficiency is that through introspection, we cannot perceive the inner workings of the brain. Thus, the view from the first person perspective creates the pervasive illusion that the mind is nonphysical. Sensing the environment requires encoding information into neural surrogates, which I conceive as contingent processes that when incorporated into conscious processes become qualitative experiences. They are cognitive shortcuts with a variable degree of isomorphism, which partially falsify reality. Thus, the what-it-is-like is not the what-it-is. The first person perspective seemings should be corrected by the objective approach provided by neuroscience. To compensate for the contingency of experiences, organisms learn to rely on the aboutness of associated phenomenal concepts. Experiences have high biological value, because even in the absence of language, they allow organisms to make intelligent choices. Qualia are also necessary to ground words and language, which are essential to develop higher forms of cognition
— id: 60234, year: 2005, vol: 147, page: 425, stat: Journal Article,

The ineffability of qualia and the word-anchoring problem
Musacchio, Jose M
2005 ;27(4):403-435 Jul, Language sciences
The ineffability of qualia and the word-anchoring problem are intimately related. Innate neural structures realize qualitative experiences that we rapidly learn to associate to their aboutness and to other events. Phylogenetically conserved neural structures provide the common endowment that serves as the bases for phenomenal knowledge and for building a virtual language-independent phenomenal-intentional lexicon, in which the 'entries' are the what-it-is-like of experiences and their 'definitions' consist in their aboutness and in their indexical reference. Qualitative experiences consist in analogue neurophysiological processes, which are ineffable simply because they cannot be duplicated in other brains through propositions or symbolic descriptions. A second virtual dictionary, the verbal-phenomenal lexicon functions as a 'bilingual' dictionary that interconnects signals, utterances and words developed by a specific culture with our common phylogenetic endowment. This grounds words in the phenomenal, establishing a bridge between language and intentionality. The third lexicon--a personal version of the regular dictionary--explains the meaning of words with definitions, but eventually, it must resort to examples to refer to the meaning of ineffable words anchored in the verbal-phenomenal lexicon. The references to qualitative experiences entered in the regular dictionary are unintelligible to individuals who do not share our genetic endowment and phenomenology, as illustrated by color blindness. The limited hardware of the brain determines the scope and the nature of our experiences. Fortunately, we can transcend the limitations of phenomenal knowledge through prepositional knowledge, which incorporates the combinatorial symbolism of language and the normative influence of science and philosophy. (journal abstract)
— id: 71151, year: 2005, vol: 27, page: 403, stat: Journal Article,

Dissolving the Explanatory Gap: Neurobiological Differences Between Phenomenal and Propositional Knowledge
Musacchio, Jose M
2002 ;3(3):331-365 Dec, Brain & mind
Discusses differences between phenomenal and propositional knowledge. The explanatory gap and the knowledge argument are rooted in the conflation of propositional and phenomenal knowledge. In addition to their fundamental epistemological differences, clinical, anatomical, pathological, and brain imaging studies demonstrate that phenomenal and propositional knowledge are fundamentally different neurobiological processes. Propositional knowledge is phylogenetically new, highly symbolic, culturally acquired, exclusively human, and expressible in different natural and artificial languages. By contrast, phenomenal knowledge consists in qualitative experiences and phenomenal concepts that provide an internal, language-independent reference to the properties of objects and the needs of the organism. Language and propositional knowledge are exclusively human attributes implemented in specific regions of the dominant hemisphere. Experiences are hard-wired neurobiological processes that can neither be transmitted nor re-created through the symbolism of propositions. The fallacy in the explanatory gap and in the knowledge argument is a fallacy of equivocation that results from ignoring fundamental neurobiological differences between phenomenal and propositional knowledge.
— id: 42052, year: 2002, vol: 3, page: 331, stat: Journal Article,

Expression of a truncated receptor protein tyrosine phosphatase kappa in the brain of an adult transgenic mouse
Shen P; Canoll PD; Sap J; Musacchio JM
1999 May 1;826(2):157-171, Brain research
Receptor protein tyrosine phosphatases (RPTPs) comprise a family of proteins that feature intracellular phosphatase domains and an ectodomain with putative ligand-binding motifs. Several RPTPs are expressed in the brain, including RPTP-kappa which participates in homophilic cell-cell interactions in vitro [Y.-P. Jiang, H. Wang, P. D'Eustachio, J.M. Musacchio, J. Schlessinger, J. Sap, Cloning and characterization of R-PTP-kappa, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region, Mol. Cell. Biol. 13 (1993) 2942-2951; J. Sap, Y.-P. Jiang, D. Friedlander, M. Grumet, J. Schlessinger, Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding, Mol. Cell. Biol. 14 (1994) 1-9]. The homology of RPTP-kappa's ectodomain to neural cell adhesion molecules indicates potential roles in developmental processes such as axonal growth and target recognition, as has been demonstrated for certain Drosophila RPTPs. The brain distribution of RPTP-kappa-expressing cells has not been determined, however. In a gene-trap mouse model with a beta-gal+neo (beta-geo) insertion in the endogenous RPTP-kappa gene, the consequent loss of RPTP-kappa's enzymatic activity does not produce any obvious phenotypic defects [W.C. Skarnes, J.E. Moss, S.M. Hurtley, R.S.P. Beddington, Capturing genes encoding membrane and secreted proteins important for mouse development, Proc. Natl. Acad. Sci. U.S.A. 92 (1995) 6592-6596]. Nevertheless, since the transgene's expression is driven by the endogenous RPTP-kappa promoter, distribution of the truncated RPTP-kappa/beta-geo fusion protein should reflect the regional and cellular expression of wild-type RPTP-kappa, and thus may identify sites where RPTP-kappa is important. Towards that goal, we have used this mouse model to map the distribution of the truncated RPTP-kappa/beta-geo fusion protein in the adult mouse brain using beta-galactosidase as a marker enzyme. Visualization of the beta-galactosidase activity revealed a non-random pattern of expression, and identified cells throughout the CNS that display RPTP-kappa promoter activity. Several neural systems highly expressed the transgene-most notably cortical, olfactory, hippocampal, hypothalamic, amygdaloid and visual structures. These well-characterized brain regions may provide a basis for future studies of RPTP-kappa function
— id: 56429, year: 1999, vol: 826, page: 157, stat: Journal Article,

GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors
Canoll PD; Musacchio JM; Hardy R; Reynolds R; Marchionni MA; Salzer JL
1996 Aug;17(2):229-243, Neuron
We show that GGF/neuregulin is a mitogen for prooligodendrocytes (O4+/O1- cells), oligodendrocytes (O4+/O1+ cells), and type-2 astrocytes. Heregulin beta 1, another neuregulin isoform, is also mitogenic. The proliferative effect of glial growth factor (GGF) does not require, but is greatly potentiated by, serum factors. GGF also promotes the survival of pro-oligodendrocytes under serum-free conditions. High levels of GGF reversibly inhibit the differentiation and lineage commitment of oligodendrocyte progenitors and, in differentiated cultures, result in loss of O1 and myelin basic protein expression. All three erbB receptors are expressed by progenitors and are activated by GGF; the relative abundance of these receptors changes during differentiation. Finally, cortical neurons release a soluble mitogen for pro-oligodendrocytes that is specifically blocked by antibodies to GGF. These results implicate the neuregulins in the neuronal regulation of oligodendrocyte progenitor proliferation, survival, and differentiation
— id: 12572, year: 1996, vol: 17, page: 229, stat: Journal Article,

Three forms of RPTP-beta are differentially expressed during gliogenesis in the developing rat brain and during glial cell differentiation in culture
Canoll PD; Petanceska S; Schlessinger J; Musacchio JM
1996 May 1;44(3):199-215, Journal of neuroscience research
In situ hybridization and Northern analysis demonstrate that the three splicing variants of RPTP-beta have different spatial and temporal patterns of expression in the developing brain. The 9.5-kb and 6.4-kb transcripts, which encode transmembrane protein tyrosine phosphatases with different extracellular domains, are predominantly expressed in glial progenitors located in the subventricular zone (SVZ). The 8.4-kb transcript, which encodes a secreted chondroitin sulfate proteoglycan (phosphacan), is expressed at high levels by more mature glia that have migrated out of the SVZ. The three transcripts are also differentially expressed in glial cell cultures; O2A progenitors express high levels of the 9.5- and 8.4-kb transcript, whereas type 1 astrocyte progenitors predominantly express the 6.4-kb transcript. C6 gliomas also express high levels of the 6.4-kb transcript. Treating C6 cells with the differentiating agent dibutyryl cyclic-AMP (DBcAMP), induces a decrease in the 6.4-kb transcript and a corresponding increase in the 8.4-kb transcript. O2A cells grown in the presence of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) remain highly proliferative and undifferentiated, and continue to express high levels of RPTP-beta. However, when O2A cells are grown in conditions that induce oligodendrocyte differentiation, there is a marked decrease in the expression of the transmembrane forms of RPTP-beta, as determined by immunofluorescence. These results demonstrate that RPTP-beta expression is regulated during glial cell differentiation and suggest that the different forms of RPTP-beta perform distinct functions during brain development
— id: 12615, year: 1996, vol: 44, page: 199, stat: Journal Article,

Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions [see comments]
Lev S; Moreno H; Martinez R; Canoll P; Peles E; Musacchio JM; Plowman GD; Rudy B; Schlessinger J
1995 Aug 31;376(6543):737-745, Nature
The protein tyrosine kinase PYK2, which is highly expressed in the central nervous system, is rapidly phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration, as well as by protein kinase C activation. Activation of PYK2 leads to modulation of ion channel function and activation of the MAP kinase signalling pathway. PYK2 activation may provide a mechanism for a variety of short- and long-term calcium-dependent signalling events in the nervous system
— id: 7926, year: 1995, vol: 376, page: 737, stat: Journal Article,

Expression of receptor protein tyrosine phosphatase-sigma (RPTP-sigma) in the nervous system of the developing and adult rat
Wang H; Yan H; Canoll PD; Silvennoinen O; Schlessinger J; Musacchio JM
1995 Jun 15;41(3):297-310, Journal of neuroscience research
The expression of receptor protein tyrosine phosphatase-sigma (RPTP-sigma) mRNA during rat development was examined by Northern blot and in situ hybridization analyses. Northern blot analysis revealed that the two transcripts (5.7 kb and 6.9 kb) had different spatial and temporal patterns of expression. The 6.9-kb transcript was more abundant during embryonic development, whereas the 5.7-kb transcript was more abundant during postnatal development and in the adult. In situ hybridization revealed that RPTP-sigma mRNA was widely expressed throughout the central and peripheral nervous system during embryonic development. Very high levels were seen in the ventricular zone, subventricular zone, cortex, dorsal root ganglia, cranial nerve ganglia, olfactory epithelium, and retina. During postnatal development the level of expression decreased in most brain regions. However, high levels continued to be seen in the hippocampus. Emulsion autoradiography revealed that the majority of RPTP-sigma mRNA is expressed in neurons. Northern analysis showed that cultured glial cells expressed the 6.9-kb transcript, but not the 5.7-kb. RPTP-sigma mRNA expression profiles were clearly distinct from those of leukocyte antigen-related protein (LAR), a closely related RPTP. The spatiotemporal pattern of RPTP-sigma mRNA expression indicates that RPTP-sigma may play a role in the development of the nervous system
— id: 56855, year: 1995, vol: 41, page: 297, stat: Journal Article,

Effects of haloperidol and reduced haloperidol on binding to sigma sites
Klein M; Cooper TB; Musacchio JM
1994 Mar 21;254(3):239-248, European journal of pharmacology
The s.c. administration of a single dose of 0.1 mg/kg of reduced haloperidol to guinea pigs produced a marked inhibition of the binding of [3H]dextromethorphan and [3H]3-(3-hydroxyphenyl)-N-(n-propyl)piperidine ([3H](+)-3-PPP) to brain. The inhibition was still evident 10 days later, and it was accompanied by residual brain levels of reduced haloperidol, and much lower levels of haloperidol. Scatchard and computer-assisted analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. In the rat, haloperidol and reduced haloperidol also produced a rapid inhibition of binding to sigma sites. Interestingly, the brain of the reduced haloperidol-treated rats contained both haloperidol and reduced haloperidol, but the levels of reduced haloperidol in the haloperidol-treated rats were undetectable. However, the inhibition observed was of comparable magnitude, indicating that the haloperidol remaining in the brain is also inhibitory. In vitro experiments showed that the inhibition produced by haloperidol and reduced haloperidol was apparently competitive, but when brain membranes were preincubated with either drug, the inhibition was noncompetitive. By contrast, the inhibition produced by dextromethorphan was always competitive. Moreover, the inhibition produced by haloperidol and reduced haloperidol could not be reversed by washing. This investigation strongly suggests that the inhibition observed after the administration of haloperidol or reduced haloperidol is not a classic agonist-induced receptor down-regulation. The results indicated that the inhibition produced is a complex phenomenon, and suggest the formation of a slowly reversible or irreversible complex with reduced haloperidol or haloperidol
— id: 6422, year: 1994, vol: 254, page: 239, stat: Journal Article,

NIH TRIAGE
MUSACCHIO, JM
1994 DEC 12 ;8(24):13-13, Scientist
— id: 52278, year: 1994, vol: 8, page: 13, stat: Journal Article,

The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system
Canoll PD; Barnea G; Levy JB; Sap J; Ehrlich M; Silvennoinen O; Schlessinger J; Musacchio JM
1993 Oct 15;75(2):293-298, Brain research. Developmental brain research
Analysis of the localization of receptor-type protein tyrosine phosphatase-beta (RPTP-beta) by in situ hybridization and immunocytochemistry indicates that it is predominantly expressed in the developing central nervous system (CNS). RPTP-beta is highly expressed in radial glia and other forms of glial cells that play an important role during development. The immunoreactivity localizes to the radial processes of these cells, which act as guides during neuronal migration and axonal elongation. The pattern of RPTP-beta expression changes with the progression of glial cell differentiation. In the adult, high levels of RPTP-beta are seen in regions of the brain where there is continued neurogenesis and neurite outgrowth. The spatial and temporal patterns of RPTP-beta expression suggest that this receptor phosphatase plays a role in morphogenesis and plasticity of the nervous system
— id: 56505, year: 1993, vol: 75, page: 293, stat: Journal Article,

The expression of receptor type tyrosine phosphatase-beta (RPTP-beta): Evidence for a role in morphogenesis and development of the nervous system
Canoll, P. D.; Barnea, G.; Levy, J. B.; Sap, J.; Silvennoinen, O.; Ehrlich, M.; Schlessinger, J.; Musacchio, J. M.
1993 ;19(1-3):1301-1301, Abstracts (Society for Neuroscience)
— id: 92600, year: 1993, vol: 19, page: 1301, stat: Journal Article,

Cloning and characterization of R-PTP-kappa, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region
Jiang YP; Wang H; D'Eustachio P; Musacchio JM; Schlessinger J; Sap J
1993 May;13(5):2942-2951, Molecular & cellular biology
We describe a new member of the receptor protein tyrosine phosphatase family, R-PTP-kappa, cDNA cloning predicts that R-PTP-kappa is synthesized from a precursor protein of 1,457 amino acids. Its intracellular domain displays the classical tandemly repeated protein tyrosine phosphatase homology, separated from the transmembrane segment by an uncharacteristically large juxta-membrane region. The extracellular domain of the R-PTP-kappa precursor protein contains an immunoglobulin-like domain and four fibronectin type III-like repeats, preceded by a signal peptide and a region of about 150 amino acids with similarity to the Xenopus A5 antigen, a putative neuronal recognition molecule (S. Takagi, T. Hsrata, K. Agata, M. Mochii, G. Eguchi, and H. Fujisawa, Neuron 7:295-307, 1991). Antibodies directed against the intra- and extracellular domains reveal that the R-PTP-kappa precursor protein undergoes proteolytic processing, following which both cleavage products remain associated. By site-directed mutagenesis, the likely cleavage site was shown to be a consensus sequence for cleavage by the processing endopeptidase furin, located in the fourth fibronectin type III-like repeat. In situ hybridization analysis indicates that expression of R-PTP-kappa in the central nervous system is developmentally regulated, with highest expression seen in actively developing areas and, in the adult, in areas capable of developmental plasticity such as the hippocampal formation and cerebral cortex. The mouse R-PTP-kappa gene maps to chromosome 10, at approximately 21 centimorgans from the centromere
— id: 13177, year: 1993, vol: 13, page: 2942, stat: Journal Article,

A novel receptor tyrosine phosphatase-sigma that is highly expressed in the nervous system
Yan H; Grossman A; Wang H; D'Eustachio P; Mossie K; Musacchio JM; Silvennoinen O; Schlessinger J
1993 Nov 25;268(33):24880-24886, Journal of biological chemistry
A novel transmembrane receptor protein tyrosine phosphatase-sigma (RPTP-sigma) was cloned from a rat brain stem cDNA library. The extracellular segment of one form of RPTP-sigma contains 824 amino acids and is composed of three immunoglobulin-like and five fibronectin type III (FNIII)-like repeats. The 627-amino acid cytoplasmic region of RPTP-sigma consists of two catalytic domains oriented in tandem. Northern blot analyses indicate that RPTP-sigma is highly expressed in the brain as two major transcripts of 5.7 and 6.9 kilobases (kb). The 5.7-kb transcript is expressed exclusively in the brain while the 6.9-kb species can be detected in the lung and heart, but at significantly lower levels. In situ hybridization studies confirm that RPTP-sigma is localized predominantly in the nervous system and can be detected in the rat as early as embryonic day 12. During embryonic development, RPTP-sigma is expressed extensively in the central and peripheral nervous systems, including the trigeminal and dorsal root ganglia as well as the retina. In adult rat brain, expression is restricted primarily to the olfactory tubercule, cerebellum, and hippocampus. Within the latter structure, RPTP-sigma is present in the pyramidal cell layer and granular layer of the dentate gyrus. Transfection of RPTP-sigma cDNA into human embryonic kidney 293 cells results in the synthesis of a protein with an apparent molecular mass of 200 kDa as detected by immunoprecipitation and immunoblot analyses using polyclonal antibodies against the FNIII-like repeats present in the extracellular domain of RPTP-sigma. The gene for RPTP-sigma has been mapped to distal chromosome 17 in the mouse
— id: 6558, year: 1993, vol: 268, page: 24880, stat: Journal Article,

High-affinity dextromethorphan and (+)-3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine binding sites in rat brain. Allosteric effects of ropizine
Klein M; Musacchio JM
1992 Mar;260(3):990-999, Journal of pharmacology & experimental therapeutics
Dextromethorphan (DM) binds to high- and low-affinity sites in the rat brain. The high-affinity DM binding is inhibited by nonnarcotic antitussives, opipramol and sigma ligands with nanomolar affinities. Computer-assisted modeling of homologous and heterologous competition studies between DM and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP] were performed at pH 8.4. These experiments confirmed the existence of the common high-affinity DM1/sigma 1 site (R1) for which DM and (+)-3-PPP have Kd values of 20 and 10 nM, respectively. DM also binds to a second high-affinity site (R2, Kd, 20 nM) for which (+)-3-PPP has only micromolar affinity. Similarly, (+)-3-PPP binds to another high-affinity site (R3, Kd, 60 nM) for which DM has micromolar affinity. The common high-affinity DM1/sigma 1 site is allosterically modulated by the anticonvulsant ropizine, and is (+)-pentazocine sensitive, as is the homologous site in the guinea pig. However, in the rat the common DM1/sigma 1 site is 10 times smaller than in the guinea pig. This explains the apparently different effects of the allosteric modifiers in both species. The multiplicity of binding sites for DM and (+)-3-PPP resolved in this investigation will help to establish the physiological role and the pharmacological potential of the different sites. Meanwhile, the pharmacological effects of DM and sigma ligands cannot be summarily attributed to any particular binding site or receptor. This investigation also demonstrates that the use of multiple labeled and unlabeled ligands, combined with computer-assisted modeling, is essential to resolve multiple binding sites with similar affinities and to characterize the complex effects of allosteric modifiers
— id: 13688, year: 1992, vol: 260, page: 990, stat: Journal Article,

SKF-525-A AND CYTOCHROME-P-450 LIGANDS INHIBIT WITH HIGH- AFFINITY THE BINDING OF [H-3] DEXTROMETHORPHAN AND SIGMA LIGANDS TO GUINEA-PIG BRAIN
Klein, M; Canoll, PD; Musacchio, JM
1991 Oct;48(6):543-550, Life sciences
The DM1/sigma-1 site binds dextromethorphan (DM) and sigma receptor ligands. The broad binding specificity of this site and its peculiar subcellular distribution prompted us to explore the possibility that this site is a member of the cytochrome P-450 superfamily of enzymes. We tested the effects of the liver microsomal monooxygenase inhibitor SKF 525-A (Proadifen), and other P-450 substrates on the binding of [H- 3]dextromethorphan, [H-3]3-(-3-Hydroxyphenyl)-N-(1- propyl)piperidine and (+)-[H-3]1,3-Di-o-tolyl-guanidine ([H- 3]DTG) to the guinea pig brain. SKF 525-A, l-lobeline and GBR- 12909 inhibited the binding of the three labeled ligands with nM affinity. Each drug has identical nM K(i) values for the high-affinity site labeled by the three ligands. This indicated that they displaced the labeled ligands from the common DM1/sigma-1 site. Debrisoquine and sparteine, prototypical substrates for liver debrisoquine 4-hydroxylase, displayed K(i) values of 9-13 and 3-4 mu-M respectively against the three labeled ligands. These results, the broad specificity of the DM1/sigma-1 binding site, and its peculiar subcellular distribution, raises the possibility that this binding site is a member of the cytochrome P-450 superfamily of isozymes, rather than a neurotransmitter receptor. These findings may have important implications for the understanding of the therapeutic, side effects and toxicity of several neurotropic drugs
— id: 32199, year: 1991, vol: 48, page: 543, stat: Journal Article,

SKF 525-A AND CYTOCHROME-P-450 LIGANDS INHIBIT THE BINDING OF [H-3] DEXTROMETHORPHAN AND SIGMA LIGANDS TO GUINEA-PIG BRAIN
MUSACCHIO, JM; KLEIN, M; CANOLL, PD
1991 MAR 11 ;5(4):A701-A701, FASEB journal
— id: 51705, year: 1991, vol: 5, page: A701, stat: Journal Article,

Computer-assisted modeling of multiple dextromethorphan and sigma binding sites in guinea pig brain
Zhou GZ; Musacchio JM
1991 Apr 25;206(4):261-269, European journal of pharmacology
Computer-assisted, simultaneous analysis of self- and cross-displacement experiments demonstrated the existence of several binding sites in guinea pig brain for dextromethorphan, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), and 1,3-di-o-tolyl guanidine (DTG). Dextromethorphan binds with high affinity to two sites (R1 Kd 50-83 and R2 Kd 8-19 nM) and with low affinity to two additional sites (R3 and R4). (+)-3-PPP binds to one high-affinity (R1 Kd 24-36 nM), to one intermediate-affinity (R3 Kd 210-320 nM), and to two (R2 and R4) low-affinity sites. DTG binds with almost identical high affinity to two different sites (R1 Kd 22-24 and R3 Kd 13-16 nM). These results confirm that dextromethorphan, (+)-3-PPP, and DTG bind to the common DM1/sigma 1 site (R1). The binding of DTG to two different sites with identical affinities precludes the use of this compound as a specific marker for sigma receptors. Besides, haloperidol displaces labeled ligands from both high-affinity DTG sites (R1 and R3) with high affinity. Thus, haloperidol sensitivity should not be used as the single criterion to identify a putative receptor. The resolution of these novel sites also may provide new insights into the multiple effects of antipsychotic drugs. In addition, this investigation has important implications regarding the methods that must be applied to characterize multiple binding sites and their relations with putative receptors
— id: 14064, year: 1991, vol: 206, page: 261, stat: Journal Article,

Autoradiographic localization of [3H]dextromethorphan (DM) in guinea pig brain: allosteric enhancement by ropizine
Canoll, P D; Smith, P R; Gottesman, S; Musacchio, J M
1990 ;328:171-174, Progress in clinical & biological research
— id: 150632, year: 1990, vol: 328, page: 171, stat: Journal Article,

Ropizine concurrently enhances and inhibits [3H]dextromethorphan binding to different structures of the guinea pig brain: autoradiographic evidence for multiple binding sites
Canoll, P D; Smith, P R; Musacchio, J M
1990 ;46(19):PL9-P16, Life sciences
Ropizine (10 microM) produces a simultaneous enhancement and inhibition of [3H]dextromethorphan (DM) high-affinity binding to different areas of the guinea pig brain. These results imply that there are two distinct types of high-affinity [3H]DM binding sites, which are present in variable proportions in different brain structures. The ropizine-enhanced [3H]DM binding type was preferentially inhibited by (+)-pentazocine. This is consistent with the presumption that the (+)-pentazocine-sensitive site is identical with the common site for DM and 3-(-3-Hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP). The second binding type, which is inhibited by ropizine and is not so sensitive to (+)-pentazocine, has not been fully characterized. This study demonstrates that the biphasic effects of ropizine are due, at least in part, to the effects of ropizine on two different types of [3H]DM binding sites. However, this study does not rule out that common DM/(+)-3-PPP site also might be inhibited by higher concentrations of ropizine
— id: 150633, year: 1990, vol: 46, page: PL9, stat: Journal Article,

COMPUTER-ASSISTED ANALYSIS OF DEXTROMETHORPHAN AND (+)-3-(-3- HYDROXYPHENYL)-N-(1-PROPYL)PIPERIDINE BINDING-SITES IN RAT- BRAIN - ALLOSTERIC EFFECTS OF ROPIZINE
Klein, M; Musacchio, JM
1990 Nov;47(18):1625-1634, Life sciences
— id: 31834, year: 1990, vol: 47, page: 1625, stat: Journal Article,

SIGMA-LIGANDS BIND IN THE GUINEA-PIG AND RAT-BRAIN TO A HIGH- AFFINITY DEXTROMETHORPHAN SITE, WHICH IS ALLOSTERICALLY MODULATED BY ROPIZINE AND PHENYTOIN
Klein, M; Zhou, G; Musacchio, JM
1990 Jul;183(6):2146-2146, European journal of pharmacology
— id: 32051, year: 1990, vol: 183, page: 2146, stat: Journal Article,

The psychotomimetic effects of opiates and the sigma receptor
Musacchio JM
1990 Jun;3(3):191-200, Neuropsychopharmacology
A critical review of the literature shows that the dysphoric and psychotomimetic side effects of sigma opiates reside in the levorotatory and not in the dextrorotatory or (+)-isomer, as currently believed. Nalorphine, levallorphan, (-)-pentazocine, (-)-3-hydroxy-N-propargylmorphinan, and MR 2034, all levorotatory opiates, produce dysphoria and psychotomimetic effects, whereas the dextrorotatory isomers of pentazocine and MR 2034 do not. Moreover, the dysphoria and psychotomimetic effects produced by racemic cyclazocine and MR 2034 are antagonized dramatically by naloxone, which is levorotatory and has no affinity for the sigma receptor as currently defined. The findings reviewed demonstrate that the psychotomimetic effects of sigma opiates are mediated by opiate receptors, the type of which has not been determined. The haloperidol sensitive sigma receptor, with higher affinity for the dextrorotatory isomers than for the sigma opiates, cannot mediate the psychotomimetic effects produced by levorotatory opiates. The conclusions derived from this review have profound implications, because a putative psychotomimetic receptor with the wrong stereospecificity will mislead future research, frustrate investigators, and confound the granting agencies
— id: 63178, year: 1990, vol: 3, page: 191, stat: Journal Article,

Autoradiographic localization of [3H]dextromethorphan in guinea pig brain: allosteric enhancement by ropizine
Canoll PD; Smith PR; Gottesman S; Musacchio JM
1989 Oct;24(2):311-328, Journal of neuroscience research
Dextromethorphan (DM) is an antitussive with anticonvulsant activity that binds to high- and low-affinity sites in guinea pig brain homogenates. We examined the autoradiographic localization of [3H]DM using the anticonvulsant ropizine, an allosteric modifier that decreases the dissociation rate of [3H]DM. Competition studies demonstrated that the binding to brain sections was identical to that of brain homogenates [Craviso and Musacchio: Mol Pharmacol 23:629-640, 1983b]. Computer-assisted quantitative analysis of the autoradiographic images demonstrated that [3H]DM binds to discrete structures throughout the brain, but with higher density in the midbrain, pons, and medulla oblongata. The most intense labeling was observed in the rhabdoid, dorsal raphe, median raphe, caudal linear raphe nuclei, and cranial motor nerve nuclei. The central gray showed moderate to high-density labeling throughout its entire rostro-caudal extent, with very high binding in the dorsal tegmental nucleus and the locus coeruleus. Moderate and high binding was also seen in several hypothalamic structures. Distinct bands of moderate binding were seen in the pyramidal cell layer of the piriform cortex, the retrosplenial cortex, the granular cell layer of the dentate gyrus, the pyramidal cell layer of the hippocampus, and the Purkinje cell layer of the cerebellum. The striking similarity between the binding distribution of [3H]DM and sigma ligands, plus competition studies in brain homogenate, support the hypothesis that DM and sigma ligands share a common high-affinity binding site [Musacchio et al: Mol Pharmacol 35:1-5, 1989]. The distribution of [3H]DM binding provides possible anatomical substrates for both the antitussive and anticonvulsant actions of DM
— id: 10479, year: 1989, vol: 24, page: 311, stat: Journal Article,

High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents
Klein M; Musacchio JM
1989 Oct;251(1):207-215, Journal of pharmacology & experimental therapeutics
Dextromethorphan (DM), a non-narcotic antitussive, binds in the guinea pig brain to specific high- and low-affinity sites with Kd values of 57 nM and 24 microM, respectively (Musacchio et al., 1988). The antitussives carbetapentane, caramiphen, butamirate and dimethoxanate competed with the high-affinity binding of [3H]DM at pH 7.4 with nanomolar Ki values. Sigma site ligands showed high affinity for [3H]DM binding sites. The rank order of potency was: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than 3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine greater than (+)-N-allylnormetazocine greater than (-)-butaclamol much greater than (+)-butaclamol (-)-N-allylnormetazocine. The antipsychotic perphenazine competed with low nanomolar Ki values, whereas rimcazole was weaker. The antidepressant opipramol and the benzomorphan (+)2'methoxyphenazocine were the most effective drugs tested, with Ki values of 0.4 nM. By contrast, MK-801 and phencyclidine hydrochloride were very weak competitors for [3H]DM binding. The diphenylalkylamines were the most effective competitors of the calcium channel blocking agents: prenylamine and cinnarizine had Ki values of 17 and 22 nM, respectively. Lidoflazine and hydroxyzine were slightly less potent, but nifedipine and the benzothiazepine diltiazem were much weaker. Potassium channel blockers inhibited DM binding in pharmacologically relevant concentrations: primaquine was the most effective with a Ki of 0.5 microM. Other antimalarial potassium channel blockers tested inhibited binding in the micromolar range. 4-Aminopyridine and tetraethylammonium had Ki values of 0.76 and 1.40 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 10491, year: 1989, vol: 251, page: 207, stat: Journal Article,

THE EFFECTS OF PROTOTYPIC-SIGMA LIGANDS ON THE BINDING OF [H-3] DEXTROMETHORPHAN TO GUINEA-PIG BRAIN
Klein, M; Paturzo, JJ; Musacchio, JM
1989 Feb 13;97(1-2):175-180, Neuroscience letters
— id: 31646, year: 1989, vol: 97, page: 175, stat: Journal Article,

Effects of dextromethorphan site ligands and allosteric modifiers on the binding of (+)-[3H]3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine
Musacchio JM; Klein M; Paturzo JJ
1989 Jan;35(1):1-5, Molecular pharmacology
Equilibrium binding analysis demonstrated that (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]3-PPP] binds in guinea pig brain homogenates to high and low affinity sites with Kd values of 25 nM and 0.9 microM, respectively. Competition studies with dextromethorphan (DM) site ligands and other drugs against (+)-[3H]3-PPP demonstrated that their Ki values and rank order of potency are identical to those found previously against [3H] DM. Most significant, ropizine produced a concentration-dependent increase in the binding of (+)-[3H]3-PPP, with an inhibitory component at high concentrations, as described previously for [3H]DM. Similarly, phenytoin increased the binding of (+)-[3H]3-PPP in the same fashion as that of [3H]DM. Computer-assisted analysis of equilibrium binding of (+)-[3H]3-PPP in the presence of 10 microM ropizine demonstrated that the binding increase produced is due to a 3-fold increase in the affinity for (+)-[3H]3-PPP. These results, and our previous finding that sigma ligands inhibit [3H] DM binding with a rank order of potency similar to that for sites labeled with (+)-[3H]3-PPP or (+)-[3H]SKF10,047 strongly suggest that sigma ligands bind to the high affinity DM site. These findings, and the inability of DM and other antitussives to produce psychotomimetic side effects, suggest that the high affinity DM sites can mediate only the nonpsychotomimetic effects of sigma ligands. However, further studies are necessary to determine the physiological role and therapeutic potential of the DM high affinity sites
— id: 10833, year: 1989, vol: 35, page: 1, stat: Journal Article,

DEXTROMETHORPHAN AND SIGMA-LIGANDS - COMMON SITES BUT DIVERSE EFFECTS
Musacchio, JM; Klein, M; Canoll, PD
1989 Nov;45(19):1721-1732, Life sciences
— id: 31662, year: 1989, vol: 45, page: 1721, stat: Journal Article,

Cross-dependence to opioid and alpha 2-adrenergic receptor agonists in NG108-15 cells
Lee S; Rosenberg CR; Musacchio JM
1988 Jan;2(1):52-55, FASEB journal
Clonidine, a partial alpha 2-agonist, has been used empirically to alleviate opiate withdrawal symptoms, but the mechanism of its effects is not completely understood. We studied the interactions of opioid and adrenergic receptor agonists in the NG108-15 cells, which are a model of opiate dependence. We determined that in these cells the adenylate cyclase (AC) [EC 4.6.1.1; ATP pyrophosphate-lyase (cyclizing) overshoot response to opioid or alpha 2-agonist withdrawal can be significantly attenuated or suppressed by the other agonist. Subsequently, the AC overshoot response can be triggered with the antagonist to the second agonist to which the cells were not dependent. These results demonstrate that convergent dependence to morphine and alpha 2 agonists can occur in a homogeneous cell population without neuronal loops. Therefore, the basic mechanisms that can account for convergent dependence in this model take place at the level of intracellular regulatory pathways that do not require neuronal networks
— id: 11276, year: 1988, vol: 2, page: 52, stat: Journal Article,

Dextromethorphan binding sites in the guinea pig brain
Musacchio JM; Klein M
1988 Jun;8(2):149-156, Cellular & molecular neurobiology
1. Dextromethorphan (DM), a dextrorotatory nonopioid antitussive, binds to specific high-affinity sites in the central nervous system. These sites are distinct from the opioid and other known neurotransmitter receptor sites. Antitussives such as carbetapentane and caramiphen also bind to DM sites with a nanomolar affinity. 2. The anticonvulsant drugs phenytoin and ropizine produce an allosteric enhancement of the binding of [3H]DM to guinea pig brain. DM, carbetapentane, and caramiphen also are efficacious anticonvulsant agents in the rat maximal electroshock seizures test, and DM enhances the anticonvulsant effects of phenytoin (PHT). 3. These results suggest that drugs that bind to the DM sites could be used alone as anticonvulsants or in combination with PHT to lower its effective dose and reduce its side effects. 4. The investigation of the DM binding sites may help to open new approaches for the treatment of convulsive disorders and to explain further some of the molecular mechanisms of neutronal excitability
— id: 11083, year: 1988, vol: 8, page: 149, stat: Journal Article,

High affinity dextromethorphan binding sites in guinea pig brain: further characterization and allosteric interactions
Musacchio JM; Klein M; Santiago LJ
1988 Nov;247(2):424-431, Journal of pharmacology & experimental therapeutics
Dextromethorphan (DM), a non-narcotic antitussive with anticonvulsant activity, binds to high (Kd, 57 nM)- and low-affinity sites (Kd, 24 microM) in the guinea pig brain. This work, done at physiological pH, expands previous results obtained at pH 8.3. Phenytoin (PHT) produces an allosteric increase in the binding of [3H]DM, which is more marked than that reported previously: PHT (100 microM,) at pH 7.4, increased the binding affinity of [3H]DM to brain homogenates 4-fold, without changing the concentration of DM sites. Moreover, ropizine (SC-13504) an anticonvulsant benzhydryl piperazine, also produced a marked concentration-dependent increase in the binding of [3H]DM, which is mediated by a decrease in the dissociation rate of [3H]DM. Importantly, the effects of ropizine are fully apparent at 10 microM, 10-fold lower than those of PHT. The effects of PHT and ropizine show that the affinity of the DM sites can be increased by other ligands, suggesting that these sites are located on macromolecules that can exist in at least two conformational states. [3H]DM also binds to peripheral tissues, but the brain displays the highest affinity. Besides, the central and peripheral sites are different as determined by competition studies with caramiphen and carbetapentane, which are DM site ligands with antitussive and anticonvulsant activity. The results reported in this communication are consistent with the hypothesis that the high-affinity DM binding sites mediate antitussive and anticonvulsant activity when occupied by the appropriate ligand
— id: 10903, year: 1988, vol: 247, page: 424, stat: Journal Article,

CARAMIPHEN - A NON-OPIOID ANTITUSSIVE WITH POTENT ANTICONVULSANT PROPERTIES IN RATS
Tortella, FC; Witkin, JM; Musacchio, JM
1988 Oct 11;155(1-2):69-75, European journal of pharmacology
— id: 31582, year: 1988, vol: 155, page: 69, stat: Journal Article,

EFFECT OF CALCIUM-CHANNEL BLOCKERS ON THE BINDING OF THE NOVEL ANTICONVULSANT DEXTROMETHORPHAN
Klein, M; Santiago, LJ; Musacchio, JM
1987 Mar 1;46(3):708-708, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 31264, year: 1987, vol: 46, page: 708, stat: Journal Article,

Allosteric modulation of dextromethorphan binding sites
Musacchio JM; Klein M; Santiago LJ
1987 Jul;26(7B):997-1001, Neuropharmacology
The nonopioid antitussives dextromethorphan (DM), carbetapentane and caramiphen are efficacious anticonvulsant agents in the rat MES test. The findings presented strongly suggest the existence of a novel allosteric mechanism by which drugs acting at two different but interacting sites, exert their effects. This mechanism has marked similarities with the gamma-aminobutyric acid (GABA)-benzodiazepine interactions, even though their binding sites are different. The allosteric interactions of dextromethorphan and phenytoin in the binding assay and the potentiation of the anticonvulsant effects of phenytoin by dextromethorphan suggest that drugs that bind to the dextromethorphan sites could be used to reduce the effective dose of phenytoin and reduce its side effects, at least those which are not an extension of its specific pharmacological actions. It is evident that the investigation of the molecular mechanisms described may help to open new approaches to understand and treat convulsive disorders, to find novel anticonvulsant drugs and to further explain some of the molecular mechanisms of neuronal excitability
— id: 11392, year: 1987, vol: 26, page: 997, stat: Journal Article,

N-ethylmaleimide blocks the modulatory effects of divalent cations and guanine nucleotides on the brain substance P receptor
Sharma PM; Musacchio JM
1987 Jun 12;138(1):9-19, European journal of pharmacology
The binding of [3H]physalaemin ([3H]PHY) to rat brain substance P receptors is modulated by cations and guanine nucleotides. [3H]PHY binding in the presence of either monovalent or divalent cations (125 mM Na2SO4 or 2.5 mM MnCl2) shows a KD of 5.9 and 5.5 nM and a Bmax of 44.4 and 63.9 fmol/mg protein respectively. In the presence of both, there is a 2-fold increase in the affinity (KD 2.8 nM) and a 25-80% increase in the Bmax (81.6 fmol/mg protein). Addition of 100 microM GTP or Gpp(NH)p in either 125 mM Na2SO4 or 2.5 mM MnCl2 or both decreases the Bmax by 25-55%. However, the receptor affinity for [3H]PHY is not significantly altered by guanine nucleotides. N-Ethylmaleimide (NEM) irreversibly inhibits the receptor binding with an IC50 of 1.0 mM, demonstrating that SH groups play a critical role in the interaction of the ligand with the receptor. If the SP receptors are protected with 1 microM PHY, NEM irreversibly inhibits the effect of divalent cations and guanine nucleotides. Analysis of [3H]PHY binding in 125 mM Na2SO4, 2.5 mM MnCl2 on membranes that were protected with 1 microM PHY and then preincubated with NEM demonstrates a variable decline in receptor number and a 2-fold decrease in the affinity (KD, from 2.8 to 6.9 nM). These observations indicate the existence of a second class of SH groups that are essential for the interaction of divalent cations and guanine nucleotides with the receptor. The blockade of the modulatory effects of divalent cations and guanine nucleotides by NEM treatment further suggests that brain SP receptors are coupled to a guanine nucleotide binding regulatory protein
— id: 62179, year: 1987, vol: 138, page: 9, stat: Journal Article,

Naloxone elicits an excitatory response in the morphine tolerant mouse vas deferens
Vargas ML; Musacchio JM; Bansinath M; Turndorf H; Puig MM
1987 ;29:109-109, Pharmacologist
— id: 47315, year: 1987, vol: 29, page: 109, stat: Journal Article,

Naloxone elicits an excitatory response in the morphine-tolerant mouse vas deferens
Vargas ML; Musacchio JM; Bansinath M; Turndorf H; Puig MM
1987 Dec;26(12):1815-1818, Neuropharmacology
The effects of naloxone on the electrically stimulated vas deferens from mice implanted with morphine (tolerant) or placebo (naive) pellets were studied. In tolerant vas deferens, naloxone produced an 86.6% increase of the twitch contractions when the preparations were stimulated with 15 V, while only a 12% increase was observed with supramaximal voltage (40 V). Naloxone had no effect at either voltage in preparations from naive animals. The effect of morphine in naive vas deferens stimulated with 15 V, was reversed by naloxone without further increase over baseline contractions. The results suggest that opioid receptors other than those located in the neuronal soma and/or coupled to adenylate cyclase may be involved in the development of dependence
— id: 11304, year: 1987, vol: 26, page: 1815, stat: Journal Article,

THE ADENYLATE-CYCLASE REBOUND RESPONSE TO NALOXONE IN THE NG108-15 CELLS - EFFECTS OF ETORPHINE AND OTHER OPIATES
MUSACCHIO, JM; GREENSPAN, DL
1986 AUG ;25(8):833-837, Neuropharmacology
— id: 41557, year: 1986, vol: 25, page: 833, stat: Journal Article,

DEXTROMETHORPHAN AND CARBETAPENTANE - CENTRALLY ACTING NONOPIOID ANTITUSSIVE AGENTS WITH NOVEL ANTICONVULSANT PROPERTIES
TORTELLA, FC; MUSACCHIO, JM
1986 SEP 24 ;383(1-2):314-318, Brain research
— id: 41351, year: 1986, vol: 383, page: 314, stat: Journal Article,

NONOPIOID ANTITUSSIVES - ANTICONVULSANT PROFILE AGAINST MAXIMAL ELECTROSHOCK (MES) SEIZURES
TORTELLA, FC; MUSACCHIO, JM
1986 MAR 1 ;45(3):677-677, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 41503, year: 1986, vol: 45, page: 677, stat: Journal Article,

Specific binding of [3H-Tyr8]physalaemin to rat submaxillary gland substance P receptor
Bahouth SW; Lazaro DM; Brundish DE; Musacchio JM
1985 Jan;27(1):38-45, Molecular pharmacology
[3H]Physalaemin [( 3H]PHY) binds to a single class of noninteracting sites on rat submaxillary gland membranes suspended in high ionic strength media with a KD of 2.7 nM, a Bmax of 240 fmol/mg of protein, and low nonspecific binding. The relative potencies of substance P (SP) and its fragments in competing with [3H]PHY correlate with their relative salivation potencies. This indicates that [3H]PHY interacts with a physiologically relevant SP receptor. In low ionic strength media, the KD of [3H]PHY does not change, but SP and some of its fragments are more potent than PHY in competing with [3H] PHY. Computer-assisted analysis of [3H]PHY and [3H]SP binding in high and low ionic strength media demonstrated that both peptides are equipotent in high ionic strength but that the affinity of SP increases by 70-fold in low ionic strength. The SP fragments that contain a basic residue in positions 1 and/or 3 also display an increased affinity in low ionic strength. These findings document that [3H]PHY binding in high ionic strength (mu = 0.6) accurately reflects the pharmacological potencies of agonists on the SP-P receptor. The binding of [3H]PHY, like that of [3H]SP, increases by the addition of divalent cations (Mg2+ greater than Ca2+ greater than Mn2+). Guanine nucleotides decrease [3H]PHY binding by decreasing the Bmax to the same level (160 fmol/mg of protein), in the presence or absence of Mg2+
— id: 62238, year: 1985, vol: 27, page: 38, stat: Journal Article,

SPECIFIC BINDING OF [H-3]SUBSTANCE-P TO THE RAT SUBMAXILLARY-GLAND - THE EFFECTS OF IONS AND GUANINE-NUCLEOTIDES
BAHOUTH, SW; MUSACCHIO, JM
1985 ;234(2):326-336, Journal of pharmacology & experimental therapeutics
— id: 41207, year: 1985, vol: 234, page: 326, stat: Journal Article,

Specific labeling of rat brain substance P receptor with [3H]physalaemin
Mohini P; Bahouth SW; Brundish DE; Musacchio JM
1985 Aug;5(8):2078-2085, Journal of neuroscience
The binding of [3H]physalaemin [( 3H]PHY) to rat brain membranes is specific, saturable and reversible in the presence of monovalent cations and peptidase inhibitors. Monovalent cations increase the binding of [3H]PHY in an ionic strength (mu)-dependent manner with an optimal effect at mu higher than 0.3. Addition of 2.5 mM MnCl2 results in a 2-fold increase in the affinity (KD) and a 40% increase in the maximal receptor density (Bmax). Scatchard analysis under these conditions indicates the existence of a single population of noninteracting sites with KD of 3.6 nM and a Bmax of 76 fmol/mg of protein. Substance P (SP) and physalaemin are equipotent in inhibiting the binding of [3H]PHY, whereas the potency of SP(2-11), SP(3-11), and SP(4-11) decreased in inverse proportion to their length. The relative affinity of the different tachykinins, SP, and SP fragments in competing with [3H]PHY correlates with their potency to stimulate several bioassay systems, indicating that [3H]PHY labels a physiologically relevant binding site that correspond to the SP-P tachykinin receptor. Guanine nucleotides completely abolish the increase in the binding of [3H]PHY produced by 2.5 mM MnCl2, but in its absence, the nucleotides reduce binding only by 15%. Guanine nucleotides reduce binding to the same level regardless of the presence or absence of the divalent cation. Regional distribution studies confirm that the density of SP receptors is maximal in the olfactory bulb, followed by the hypothalamus, striatum, hippocampus, cortex, and cerebellum
— id: 62276, year: 1985, vol: 5, page: 2078, stat: Journal Article,

SULFHYDRYL-REAGENTS BLOCK THE REGULATORY EFFECTS OF DIVALENT-CATIONS AND GUANINE (G) NUCLEOTIDES ON THE BRAIN TACHYKININ SP-P RECEPTOR
Musacchio, JM; Narang, PM; Bahouth, SW
1985 ;44(5):1627-1627, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 30954, year: 1985, vol: 44, page: 1627, stat: Journal Article,

DEXTROMETHORPHAN, A NON-OPIOID ANTITUSSIVE, PROTECTS AGAINST MES SEIZURES IN RATS AND POTENTIATES THE ANTICONVULSANT ACTION OF DIPHENYLHYDANTOIN
Tortella, FC; Musacchio, JM
1985 ;25(6):458-458, Journal of clinical pharmacology
— id: 30843, year: 1985, vol: 25, page: 458, stat: Journal Article,

SPECIFIC BINDING OF A I-125-LABELED SUBSTANCE-P ANALOG TO RAT SUBMAXILLARY-GLAND
BAHOUTH, SW; STEWART, JM; MUSACCHIO, JM
1984 ;230(1):116-123, Journal of pharmacology & experimental therapeutics
— id: 41073, year: 1984, vol: 230, page: 116, stat: Journal Article,

THE EFFECT OF TOLERANCE ON OPIATE DEPENDENCE AS MEASURED BY THE ADENYLATE-CYCLASE REBOUND RESPONSE TO NALOXONE IN THE NG108-15 MODEL SYSTEM
GREENSPAN, DL; MUSACCHIO, JM
1984 ;5(1-3):41-44, Neuropeptides
— id: 41262, year: 1984, vol: 5, page: 41, stat: Journal Article,

HIGH-AFFINITY DEXTROMETHORPHAN BINDING-SITES IN GUINEA-PIG BRAIN .1. INITIAL CHARACTERIZATION
Craviso, GL; Musacchio, JM
1983 ;23(3):619-628, Molecular pharmacology
— id: 30653, year: 1983, vol: 23, page: 619, stat: Journal Article,

HIGH-AFFINITY DEXTROMETHORPHAN BINDING-SITES IN GUINEA-PIG BRAIN .2. COMPETITION EXPERIMENTS
Craviso, GL; Musacchio, JM
1983 ;23(3):629-640, Molecular pharmacology
— id: 30654, year: 1983, vol: 23, page: 629, stat: Journal Article,

THE DETERMINATION OF DISSOCIATION-CONSTANTS FOR SUBSTANCE-P AND SUBSTANCE-P ANALOGS IN THE GUINEA-PIG ILEUM BY PHARMACOLOGICAL PROCEDURES
Lin, CW; Musacchio, JM
1983 ;23(3):558-562, Molecular pharmacology
— id: 30652, year: 1983, vol: 23, page: 558, stat: Journal Article,

THE DETERMINATION OF DISSOCIATION-CONSTANTS FOR SUBSTANCE-P AND SUBSTANCE-P ANALOGS IN THE GUINEA-PIG ILEUM BY PHARMACOLOGICAL PROCEDURES
LIN, CW; MUSACCHIO, JM
1983 ;42(3):497-497, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40726, year: 1983, vol: 42, page: 497, stat: Journal Article,

FAILURE OF OPIATES TO INCREASE THE HYDROLYSIS OF GTP IN INTACT NEUROBLASTOMA-GLIOMA NG108-15 CELLS
MUSACCHIO, JM; SCHEN, C
1983 ;42(3):498-498, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40727, year: 1983, vol: 42, page: 498, stat: Journal Article,

FAILURE OF OPIATES TO INCREASE THE HYDROLYSIS OF GTP IN NEUROBLASTOMA-GLIOMA 108-15 CELLS
Musacchio, JM; Schen, C
1983 ;33(9):879-887, Life sciences
— id: 30624, year: 1983, vol: 33, page: 879, stat: Journal Article,

PREPARATION AND PURIFICATION OF TRITIATED DEXTROMETHORPHAN
CRAVISO, GL; NODAR, R; MUSACCHIO, JM
1982 ;5(12):2311-2320, Journal of liquid chromatography
— id: 40366, year: 1982, vol: 5, page: 2311, stat: Journal Article,

FADING AND TACHYPHYLAXIS TO THE CONTRACTILE EFFECTS OF SUBSTANCE-P IN THE GUINEA-PIG ILEUM
HUIDOBROTORO, JP; CHELALA, CA; BAHOUTH, S; NODAR, R; MUSACCHIO, JM
1982 ;81(1):21-34, European journal of pharmacology
— id: 40405, year: 1982, vol: 81, page: 21, stat: Journal Article,

HYDROLYSIS OF SUBSTANCE-P AND BRADYKININ BY BLACK-WIDOW SPIDER VENOM GLAND EXTRACT
HUIDOBROTORO, JP; CHELALA, CA; MUSACCHIO, JM
1982 ;31(20):3323-3328, Biochemical pharmacology
— id: 40373, year: 1982, vol: 31, page: 3323, stat: Journal Article,

PHENYTOIN (DIPHENYLHYDANTOIN) ENHANCES THE BINDING OF DEXTROMETHORPHAN TO GUINEA-PIG BRAIN
CRAVISO, GL; MUSACCHIO, JM
1981 ;40(3):324-324, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40245, year: 1981, vol: 40, page: 324, stat: Journal Article,

NALOXONE REVERSAL OF INSULIN-INDUCED HYPOTENSION IN RESERPINE PRETREATED RATS
HUIDOBROTORO, JP; MUSACCHIO, JM
1981 ;251(2):310-321, Archives internationales de pharmacodynamie & de therapie
— id: 40322, year: 1981, vol: 251, page: 310, stat: Journal Article,

"CARAMIPHEN, A MUSCARINIC BLOCKING-AGENT, COMPETES FOR DEXTROMETHORPHAN BINDING-SITES IN GUINEA-PIG BRAIN"
MUSACCHIO, JM; CRAVISO, GL
1981 ;40(3):320-320, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40244, year: 1981, vol: 40, page: 320, stat: Journal Article,

HIGH-AFFINITY BINDING OF THE ANTITUSSIVE DEXTROMETHORPHAN TO GUINEA-PIG BRAIN
Craviso, GL; Musacchio, JM
1980 ;65(4):451-453, European journal of pharmacology
— id: 27974, year: 1980, vol: 65, page: 451, stat: Journal Article,

Opioid peptides in the guinea pig ileum
Musacchio JM; Puig MM; Casper M; Nodar R
1980 ;22(1):313-321, Advances in biochemical psychopharmacology
— id: 45677, year: 1980, vol: 22, page: 313, stat: Journal Article,

INHIBITION OF ENKEPHALIN DEGRADATION IN GUINEA-PIG ILEUM
CRAVISO, GL; MUSACCHIO, JM
1978 ;23(20):2019-2029, Life sciences
— id: 40033, year: 1978, vol: 23, page: 2019, stat: Journal Article,

Electrically induced opiate-like inhibition of the guinea-pig ileum: cross-tolerance to morphine
Puig MM; Gascon P; Musacchio JM
1978 Sep;206(2):289-302, Journal of pharmacology & experimental therapeutics
The guinea-pig myenteric plexus-longitudinal muscle (MPLM) preparation electrically stimulated at 0.1 Hz is very sensitive to the inhibitory effects of opiates. We used this preparation to detect an inhibitory response (IR) which was produced by electrical stimulation at 5 to 20 Hz. The magnitude and duration of the IR are determined by the parameters of the stimulation, mainly by the frequency and duration of the period of stimulation. Maximal IR is obtained with symmetrical biphasic stimuli of 2 msec duration and supramaximal voltage at 20 Hz applied for a period of about 5 min. The IR is calcium-dependent, cannot be attenuated by washing and is mediated by several components. About 55 to 70% of the IR can be reversed by specific narcotic antagonists and therefore it is considered to be produced by the release of endorphins. There are at least two additional components, one small, adrenergic in nature, and a third one which has not been identified. The offset rate of the IR is measured in minutes, while enkephalin and human beta-endorphin have half-lives of 10 and 85 sec, respectively, after washing. This suggests that the endorphin that mediates the opiate component of the IR may be a different one with slower offset rates. Myenteric plexus-longitudinal muscle strips obtained from guinea pigs which were made tolerant to morphine by subcutaneous implantation of three pellets were cross-tolerant to the opiate component of the IR elicited by electrical stimulation
— id: 45678, year: 1978, vol: 206, page: 289, stat: Journal Article,

DURATION OF ELECTRICALLY INDUCED OPIATE-LIKE INHIBITION OF GUINEA-PIG ILEUM
Puig, MM; Musacchio, JM
1978 ;37(3):310-310, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 29843, year: 1978, vol: 37, page: 310, stat: Journal Article,

Quinonoid dihydropterin reductase--II. Regional and subcellular distribution of rat brain enzyme
Snady H; Musacchio JM
1978 ;27(15):1947-1953, Biochemical pharmacology
— id: 63321, year: 1978, vol: 27, page: 1947, stat: Journal Article,

Quinonoid dihydropterin reductase-I. Purification and characterization of the bovine brain enzyme
Snady H; Musacchio JM
1978 ;27(15):1939-1945, Biochemical pharmacology
— id: 63320, year: 1978, vol: 27, page: 1939, stat: Journal Article,

The effect of enkephalin and enkephalin analogs on the guinea-pig ileum and rat brain opilate receptor
Puig MM; Gascon P; Craviso GL; Bjur RA; Matsueda G; Stewart JM; Musacchio JM
1977 Apr;226(1):69-80, Archives internationales de pharmacodynamie & de therapie
We have synthesized the two naturally occurring enkephalins (Methionine-Enkephalin and Leucine-Enkephalin) as well as four other analogs (Methinonine-Enkephalin amide, S-Benzyl sulphonium analog of Methionine-Enkephalin, 3-Benzyl-tyrosine analog of Methionine-Enkephalin and 3-Benzyl-tyrosine analog of Leucine-Enkephalin) in order to study their relative potency and their inactivation of different tissues. Morphine-like activity of the peptides was determined by measuring their inhibitory effect in the guinea-pig ileum and their interaction with the brain opiate receptor; the order of affinity of the three most active peptides (Methionine-Enkephalin amide greater than Methionine-Enkephalin greater than Leucine-Enkephalin) for the rat brain opiate receptor was found to be the same in the guinea-pig ileum. The rate of inactivation of the peptides was also studied in the guinea-pig ileum and in the rat brain membrane preparation. Methionine-Enkephalin amide was relatively more resistant to the ileum peptidases than the other peptides, but was destroyed at the same rate by brain membranes; this variation in inactivation of Methionine-Enkephalin amide probably indicates the presence of differnet peptidases in each tissue preparation
— id: 45680, year: 1977, vol: 226, page: 69, stat: Journal Article,

Endogenous opiate receptor ligand: electrically induced release in the guinea pig ileum
Puig MM; Gascon P; Craviso GL; Musacchio JM
1977 Feb 28;195(4276):419-420, Science
Opiate receptors mediate the electrically evoked inhibition of the myenteric plexus-longitudinal muscle preparation of the guinea pig ileum. The electrically induced activation of the opiate receptor was produced by a prolonged simulation at 10 hertz and provides the first evidence that an endogenous opiate receptor ligand is released by nerve stimulation. The specificity of the phenomenon was demonstrated by the reversal obtained with the narcotic antagonists naloxone, naltrexone, and GPA 1843; GPA 1847, the (+)-isomer of 1843, did not cause reversal. The model system described should be useful for the study of the storage, synthesis, and release of endorphins
— id: 45681, year: 1977, vol: 195, page: 419, stat: Journal Article,

Endorphin release: cross tolerance to morphine
Puig MM; Gascon P; Musacchio JM
1977 Oct 15;45(2):205-206, European journal of pharmacology
— id: 45679, year: 1977, vol: 45, page: 205, stat: Journal Article,

OPIATE RECEPTOR ACTIVATION BY ELECTRICAL-STIMULATION - EVIDENCE FOR ENDORPHIN RELEASE BY NERVE-STIMULATION
PUIG, MM; GASCON, P; CRAVISO, GL; MUSACCHIO, JM
1977 ;36(3):1010-1010, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 40007, year: 1977, vol: 36, page: 1010, stat: Journal Article,

Opiate receptor: irreversible inactivation by an alkylating local anesthetic
Craviso GL; Musacchio JM
1976 Apr 15;18(8):821-827, Life sciences
— id: 62234, year: 1976, vol: 18, page: 821, stat: Journal Article,

COMPETITIVE INHIBITION OF STEREOSPECIFIC OPIATE BINDING BY LOCAL-ANESTHETICS IN MOUSE-BRAIN
Craviso, GL; Musacchio, JM
1975 ;16(12):1803-1808, Life sciences
— id: 28604, year: 1975, vol: 16, page: 1803, stat: Journal Article,

INTERACTIONS BETWEEN MORPHINE, ADENOSINE AND ATP AND EFFECTS OF PHOSPHODIESTERASE INHIBITORS ON FIELD STIMULATED GUINEA-PIG ILEUM
Gintzler, AR; Musacchio, JM
1975 ;34(3):298-298, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 28555, year: 1975, vol: 34, page: 298, stat: Journal Article,

INTERACTIONS OF MORPHINE, ADENOSINE, ADENOSINE-TRIPHOSPHATE AND PHOSPHODIESTERASE INHIBITORS ON FIELD-STIMULATED GUINEA-PIG ILEUM
GINTZLER, AR; MUSACCHIO, JM
1975 ;194(3):575-582, Journal of pharmacology & experimental therapeutics
— id: 98734, year: 1975, vol: 194, page: 575, stat: Journal Article,

CATECHOLAMINE BIOSYNTHESIS - PRODUCTION OF ANTIBODIES TO QUINONOID DIHYDROPTERIN REDUCTASE FROM BOVINE BRAIN
Snady, H; Joh, T; Musacchio, J; Reis, D
1975 ;34(3):747-747, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 28564, year: 1975, vol: 34, page: 747, stat: Journal Article,

FAILURE OF PROSTAGLANDINS TO PARTICIPATE IN INHIBITORY RESPONSE OF GUINEA-PIG ILEUM TO MORPHINE
Gintzler, AR; Musacchi[...], JM
1974 ;33(3):502-502, Federation Proceedings (Federation of American Societies for Experimental Biology)
— id: 28388, year: 1974, vol: 33, page: 502, stat: Journal Article,

INTERACTION BETWEEN SEROTONIN AND MORPHINE IN GUINEA-PIG ILEUM
Gintzler, AR; Musacchi[...], JM
1974 ;189(2):484-492, Journal of pharmacology & experimental therapeutics
— id: 28341, year: 1974, vol: 189, page: 484, stat: Journal Article,

INTERACTIONS BETWEEN 5HT AND MORPHINE IN GUINEA-PIG ILEUM
GINTZLER, A; MUSACCHI.J
1973 ;15(2):202-202, Pharmacologist
— id: 46757, year: 1973, vol: 15, page: 202, stat: Journal Article,

LSD and focal cerebral lesions. Behavioral and EEG effects in patients with sensory defects
Korein, J; Musacchio, J M
1968 Feb;18(2):147-152, Neurology
— id: 90116, year: 1968, vol: 18, page: 147, stat: Journal Article,

Inhibition of dopamine-beta-hydroxylase by disulfiram in vivo
Musacchio, J M; Goldstein, M; Anagnoste, B; Poch, G; Kopin, I J
1966 Apr;152(1):56-61, Journal of pharmacology & experimental therapeutics
— id: 117417, year: 1966, vol: 152, page: 56, stat: Journal Article,