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

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 (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. 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 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. 4 In neurons from CMT mice, there were significant reductions in P/Q-type (P=0.007) and L-type (P=0.002) ICa 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 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. British Journal of Pharmacology (2006) 148, 947–955. doi:10.1038/sj.bjp.0706820