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 ( 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 n M ) and vehicle (EC 50 320 n M ) 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.British Journal of Pharmacology (2006) 148 , 947–955. doi: 10.1038/sj.bjp.0706820