Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine.
The midbrain periaqueductal gray (PAG) is a major site of opioid analgesic action, and a significant site of cellular adaptations to chronic morphine treatment (CMT). We examined mu-opioid receptor (MOP) regulation of voltage-gated calcium channel currents (I(Ca)) and G-protein-activated K channel currents (GIRK) in PAG neurons from CMT mice. Mice were injected s.c. with 300 mg kg(-1) of morphine base in a slow release emulsion three times over 5 days, or with emulsion alone (vehicles). This protocol produced significant tolerance to the antinociceptive effects of morphine in a test of thermal nociception. Voltage clamp recordings were made of I(Ca) in acutely isolated PAG neurons and GIRK in PAG slices. The MOP agonist DAMGO (Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin) inhibited I(Ca) in neurons from CMT mice (230 nM) with a similar potency to vehicle (150 nM), but with a reduced maximal effectiveness (37% inhibition in vehicle neurons, 27% in CMT neurons). Inhibition of I(Ca) by the GABA(B) agonist baclofen was not altered by CMT. Met-enkephalin-activated GIRK currents recorded in PAG slices were significantly smaller in neurons from CMT mice than vehicles, while GIRK currents activated by baclofen were unaltered. These data demonstrate that CMT-induced antinociceptive tolerance is accompanied by homologous reduction in the effectiveness of MOP agonists to inhibit I(Ca) and activate GIRK. Thus, a reduction in MOP number and/or functional coupling to G proteins accompanies the characteristic cellular adaptations to CMT previously described in PAG neurons.
Bagley
Elena E
EE
Pain Management Research Institute, E25, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, Australia.
Chieng
Billy C H
BC
Christie
MacDonald J
MJ
Connor
Mark
M
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism / Q000502:physiology
D000701:Analgesics, Opioid; D015220:Calcium Channels; D018755:GABA Agonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine; D001418:Baclofen