THE ANALGESIC POTENCY OF DEXMEDETOMIDINE IS ENHANCED AFTER NERVE INJURY - A POSSIBLE ROLE FOR PERIPHERAL ALPHA(2)-ADRENOCEPTORS

This study investigated the analgesic potency and site of action of sy stemic dexmedetomidine, a selective alpha(2)- adrenoceptor (alpha(2)AR ) agonist, in normal and neuropathic rats. Ligation of the L5-6 spinal nerves produced a chronic mechanical and thermal neuropathic hyperalg esia in rats. von Frey fibers and a thermoelectric Peltier device were used to measure mechanical and heat withdrawal thresholds over the hi ndpaw. Systemic dexmedetomidine dose-dependently increased the mechani cal and thermal thresholds in the control animals (50% effective dose [ED50] 144 and 180 mu g/kg intraperitoneally [LP], respectively). Neur opathic animals responded to much smaller doses of dexmedetomidine wit h mechanical and thermal ED50 values of 52 and 29 mu g/kg IF, respecti vely. There was no difference between the control and neuropathic anim als with respect to dexmedetomidine-evoked sedation, as determined by decreased grid crossings in an open-field activity chamber (E-50 12 an d 9 mu g/kg IP, respectively). Atipamezole, a selective alpha(2)AR ant agonist, blocked the analgesic and sedative actions of dexmedetomidine in both the neuropathic and control animals. However, L-659,066, a pe ripherally restricted alpha(2)AR antagonist, could only block the anal gesic actions of dexmedetomidine in the neuropathic rats, with no effe ct in control animals. In conclusion, nerve injury enhanced the analge sic but not the sedative potency of systemic dexmedetomidine and may h ave shifted the site of alpha(2) analgesic action to outside the blood -brain barrier. Implications: We tested the analgesic efficacy of the alpha(2) agonist dexmedetomidine in normal and nerve-injured rats. The analgesic potency of dexmedetomidine was enhanced after nerve injury with a site of action outside the central nervous system. Peripherally restricted alpha(2) agonists may be useful in the management of neuro pathic pain.