Chronic neuropathic pain in mice reduces mu-opioid receptor-mediated G-protein activity in the thalamus

摘要

Neuropathic pain is a debilitating condition that is often difficult to treat using conventional pharmacological interventions and the exact mechanisms involved in the establishment and maintenance of this type of chronic pain have yet to be fully elucidated. The present studies examined the effect of chronic nerve injury on mu-opioid receptors and receptor-mediated G-protein activity within the supraspinal brain regions involved in pain processing of mice. Chronic constriction injury (CCI) reduced paw withdrawal latency, which was maximal at 10 days post-injury. [d-Ala2,(N-Me)Phe4,Gly5-OH] enkephalin (DAMGO)-stimulated [~(35)S]GTP-gammaS binding was then conducted at this time point in membranes prepared from the rostral ACC (rACC), thalamus and periaqueductal grey (PAG) of CCI and sham-operated mice. Results showed reduced DAMGO-stimulated [~(35)S] GTP7S binding in the thalamus and PAG of CCI mice, with no change in the rACC. In thalamus, this reduction was due to decreased maximal stimulation by DAMGO, with no difference in EC_(50) values. In PAG, however, DAMGO E_(max) values did not significantly differ between groups, possibly due to the small magnitude of the main effect. [~3H]Naloxone binding in membranes of the thalamus showed no significant differences in B_(max) values between CCI and sham-operated mice, indicating that the difference in G-protein activation did not result from differences in n-opioid receptor levels. These results suggest that CCI induced a region-specific adaptation of mu-opioid receptor-mediated G-protein activity, with apparent desensitization of the mu-opioid receptor in the thalamus and PAG and could have implications for treatment of neuropathic pain.