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

摘要

1 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 (I_(Ca)) in small trigeminal ganglion (TG) neurons from mice chronically treated with morphine and measured changes in μ-opioid receptor mRNA levels in whole TG. 2 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). 3 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 μ-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. 4 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. 5 μ-Opioid receptor mRNA levels were not altered by CMT. 6 These data demonstrate that CMT produces a significant reduction of the effectiveness of μ-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.