Decreased μ-opioid receptor signalling and a reduction in calcium current density in sensory neurons from chronically morphine-treated mice

摘要

class="enumerated" style="list-style-type:decimal">Sensory neurons are a major site of opioid analgesic action, but the effect of chronic morphine treatment (CMT) on μ-opioid receptor function in these cells is unknown. We examined μ-opioid receptor modulation of calcium channel currents (ICa) in small trigeminal ganglion (TG) neurons from mice chronically treated with morphine and measured changes in μ-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 ICa in neurons from CMT (EC50 300 nM) and vehicle (EC50 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 μ-opioid agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol enkephalin (DAMGO). Inhibition of ICa by the GABAB 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) ICa density.μ-Opioid receptor mRNA levels were not altered by CMT.These data demonstrate that CMT produces a significant reduction of the effectiveness of μ-opioid agonists to inhibit ICa in TG sensory neurons, accompanied by a reduction in ICa density. Thus, adaptations in sensory neurons may mediate some of the tolerance to the antinociceptive effects of morphine that develop during systemic administration.