Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine

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Abstract
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 μ‐opioid receptor (MOP) regulation of voltage‐gated calcium channel currents (ICa) 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 ICa 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 ICa 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 ICa by the GABAB 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 ICa 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. British Journal of Pharmacology (2005) 146, 68–76. doi:10.1038/sj.bjp.0706315

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