title: Functional compartmentalization of opioid desensitization in primary sensory neurons.
abstract: The cellular correlates of desensitization or tolerance are poorly understood. To address this, we studied acute and long-term mu-opioid desensitization, with respect to Ca(2+) currents, in cultured rat dorsal root ganglion (DRG) neurons. Exposure of DRG neurons to the mu-agonist [D-Ala(2),N-MePhe(4), Gly-ol(5)]-enkephalin (DAMGO; 3 microM) reduced whole-cell currents approximately 35%, but with continued agonist application, 52% of the response was lost over 10 to 12 min. In contrast, exposure of DRG neurons to DAMGO for 24 h resulted in a nearly complete loss of Ca(2+) channel regulation after washing and re-exposure to DAMGO. Responses to the gamma-aminobutyric acid(B) agonist baclofen were not affected in these neurons. Acute desensitization preferentially affected the voltage-sensitive component of mu-opioid and gamma-aminobutyric acid(B) responses. Facilitation of both the DAMGO- and baclofen-inhibited current by a strong depolarizing prepulse was significantly attenuated in acutely desensitized neurons. Because G(betagamma)-subunits mediate neurotransmitter-induced changes in channel voltage-dependent properties, these data suggest an altered interaction of the G(betagamma)-subunit with the Ca(2+) channel. Block of N-type Ca(2+) channels with omega-conotoxin GVIA revealed a component of the opioid response that did not desensitize over 10 min. We conclude that acute and long-term mu-opioid desensitization in DRG neurons occurs by different mechanisms. Acute desensitization is heterologous and functionally compartmentalized: the pathway targeting non-N-type channels is relatively resistant to the early effects of continuous agonist exposure; the pathway targeting N-type channels in a largely voltage-insensitive manner is partially desensitized; and the pathway targeting N-type channels in a largely voltage-sensitive manner is completely desensitized.
authors.affiliation: Departments of Neurology and Pharmacology & Physiology, University of Rochester School of Medicine & Dentistry, New York, USA. gary_samoriski@urmc.rochester.edu
authors.forename: G M
authors.initials: GM
authors.lastname: Samoriski
authors.forename: R A
authors.initials: RA
authors.lastname: Gross
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000145:classification / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000502:physiology; D002478:Cells, Cultured; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D018080:Receptors, GABA-B; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020866:omega-Conotoxin GVIA; D019204:GTP-Binding Proteins