DIFFERENTIAL CONTRIBUTION OF DESCENDING CONTROLS TO THE ANTINOCICEPTIVE ACTIONS OF KAPPA-OPIOID AND MU-OPIOID, AN ANALYSIS OF FORMALIN-EVOKED C-FOS EXPRESSION

In this study, the effect of intracerebroventricular (icv) administrat ion of (5R)-(5 alpha,7 alpha,8 nyl)-1-oxaspiro[4,5]dec-8-yl]-4-benzofu rnacetamide monohydrochloride (Cl-977) on pain behaviors and on spinal cord fos-like immunoreactivity (FLl) evoked by unilateral formalin in jection into the hindpaw of rats was examined. Intracerebroventricular administration of Cl-977 (0.13-13.00 nmol) produced a dose-dependent inhibition of formalin-evoked pain behaviors, with significant inhibit ion after 1.30, 4.40 and 13.00 nmol. The estimated ED(50) for icv Cl-9 77 inhibition of formalin-evoked behaviors was 0.95 nmol and the E(max ) was 53%. The inhibitory effect of 4.40 nmol of icv Cl-977 on formali n-evoked behaviors was prevented by either pretreatment with the kappa selective antagonist nor-binaltorphimine (10 or 100 nmol) or coadmini stration of the opiate receptor antagonist, naloxone (30 nmol). The lo west dose of icv Cl-977 tested (0.13 nmol) produced a 50% reduction in FLl in the superficial laminae but did not inhibit the expression of FLl in any other regions of the spinal cord. The fos-inhibitory effect of low-dose icy Cl-977 in the superficial cord was reversed by coadmi nistration of naloxone (30 nmol). Higher doses of icy Cl-977 that supp ressed formalin-evoked behaviors did not inhibit the expression of FLl in any region of the spinal cord. Finally, neither the inhibitory eff ect of 4.40 nmol Cl-977 on formalin-evoked behaviors nor the formalin- evoked pattern of FLl expression in the spinal cord of rats treated wi th this dose of Cl-977 was affected by lesions of the dorsolateral fun iculus. These results provide the first evidence that supraspinal kapp a receptor-mediated antinociception is not dependent on the integrity of the dorsolateral funiculus and may be mediated exclusively at the s upraspinal level, suggesting that there are multiple mechanisms throug h which opioids can evoke antinociceptive effects.