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

ABSTRACT: Sensory neurons are a major site of opioid analgesic action, but the effect of chronic morphine treatment (CMT) on mu-opioid receptor function in these cells is unknown. We examined mu-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 mu-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 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 mu-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. 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.mu-Opioid receptor mRNA levels were not altered by CMT. These data demonstrate that CMT produces a significant reduction of the effectiveness of mu-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.

SUBMITTER: Johnson EE 

PROVIDER: S-EPMC1751919 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature