Lack of cross-tolerance between the antinociceptive effects of systemic morphine and asimadoline, a peripherally-selective kappa-opioid agonist, in CCI-neuropathic rats.

The development of tolerance following repeated doses of morphine hinders the treatment of clinical pain. We have previously shown that morphine tolerance develops in neuropathic rats without cross-tolerance to a systemic kappa-opioid agonist; in the current work, using paw-pressure vocalization thresholds, we studied the antinociceptive effect of the peripherally-selective kappa (kappa)-opioid agonist, asimadoline, in both morphine-tolerant and opioid-naïve rats 2 weeks after sciatic nerve injury. In naïve rats, intraplantar (i.pl.) injection of asimadoline into the nerve-injured paw, at doses of 10, 15 and 20 (but not 30) microg, dose-dependently relieved the mechanical allodynia-like behaviour. The kappa-opioid antagonist, norbinaltorphimine, (30 microg, i.pl.) reversed this action; injection of asimadoline (15 microg) into the contralateral paw (i.pl.) or i.v., however, had no effect. These results confirm that at low doses, asimadoline exerts its action only in the periphery. In morphine-tolerant rats (after 10 mg/kg s.c. , twice daily for 4 days) and naïve, saline-pretreated rats, asimadoline (15 microg, i.pl.) relieved the mechanical allodynia-like behaviour to the same extent, indicating no cross-tolerance between morphine and the peripherally-selective drug. Our findings show promise for the treatment of neuropathic pain with low doses of peripherally-selective kappa-opioids.