title: Decreased mu-opioid receptor signalling and a reduction in calcium current density in sensory neurons from chronically morphine-treated mice.
abstract: Sensory neurons are a major site of opioid analgesic action, but the effect of chronic morphine treatment (CMT) on mu-opioid receptor function in these cells is unknown. We examined mu-opioid receptor modulation of calcium channel currents (I(Ca)) in small trigeminal ganglion (TG) neurons from mice chronically treated with morphine and measured changes in mu-opioid receptor mRNA levels in whole TG. Mice were injected subcutaneously with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). CMT mice had a significantly reduced response to the acute antinociceptive effects of 30 mg kg(-1) morphine compared with controls (P=0.035).Morphine inhibited I(Ca) in neurons from CMT (EC(50) 300 nM) and vehicle (EC(50) 320 nM) mice with similar potency, but morphine's maximum effect was reduced from 36% inhibition in vehicle to 17% in CMT (P<0.05). Similar results were observed for the selective mu-opioid agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO). Inhibition of I(Ca) by the GABA(B) agonist baclofen was unaffected by CMT. In neurons from CMT mice, there were significant reductions in P/Q-type (P=0.007) and L-type (P=0.002) I(Ca) density.mu-Opioid receptor mRNA levels were not altered by CMT. These data demonstrate that CMT produces a significant reduction of the effectiveness of mu-opioid agonists to inhibit I(Ca) in TG sensory neurons, accompanied by a reduction in I(Ca) density. Thus, adaptations in sensory neurons may mediate some of the tolerance to the antinociceptive effects of morphine that develop during systemic administration.
authors.affiliation: Pain Management Research Institute, E25, Kolling Institute, University of Sydney at Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales 2065, Australia.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Johnson
authors.forename: Billy
authors.initials: B
authors.lastname: Chieng
authors.forename: Ian
authors.initials: I
authors.lastname: Napier
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002469:Cell Separation; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D017450:Receptors, Opioid, mu / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000187:drug effects; D058308:Receptors, Prostaglandin E, EP3 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007473:Ion Channels; C545648:Ptger3 protein, mouse; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D009020:Morphine; D019204:GTP-Binding Proteins