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.