Differential contribution of descending controls to the antinociceptive actions of kappa and mu opioids: an analysis of formalin-evoked C-fos expression.
In this study, the effect of intracerebroventricular (icv) administration of (5R)-(5 alpha, 7 alpha, 8 beta)-N-methyl-N-[7-(1-pyrrolindinyl)-1- oxaspiro[4,5]dec-8-yl]-4-benzofurnacetamide monohydrochloride (Cl-977) on pain behaviors and on spinal cord fos-like immunoreactivity (FLI) evoked by unilateral formalin injection 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 inhibition after 1.30, 4.40 and 13.00 nmol. The estimated ED50 for icv Cl-977 inhibition of formalin-evoked behaviors was 0.95 nmol and the Emax was 53%. The inhibitory effect of 4.40 nmol of icv Cl-977 on formalin-evoked behaviors was prevented by either pretreatment with the kappa selective antagonist nor-binaltorphimine (10 or 100 nmol) or coadministration of the opiate receptor antagonist, naloxone (30 nmol). The lowest dose of icv Cl-977 tested (0.13 nmol) produced a 50% reduction in FLI in the superficial laminae but did not inhibit the expression of FLI in any other regions of the spinal cord. The fos-inhibitory effect of low-dose icv Cl-977 in the superficial cord was reversed by coadministration of naloxone (30 nmol). Higher doses of icv Cl-977 that suppressed formalin-evoked behaviors did not inhibit the expression of FLI in any region of the spinal cord. Finally, neither the inhibitory effect of 4.40 nmol Cl-977 on formalin-evoked behaviors nor the formalin-evoked pattern of FLI expression in the spinal cord of rats treated with this dose of Cl-977 was affected by lesions of the dorsolateral funiculus. These results provide the first evidence that supraspinal kappa receptor-mediated antinociception is not dependent on the integrity of the dorsolateral funiculus and may be mediated exclusively at the supraspinal level, suggesting that there are multiple mechanisms through which opioids can evoke antinociceptive effects.
Gogas
K R
KR
Department of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Charlestown, USA.
Levine
J D
JD
Basbaum
A I
AI
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis* / Q000276:immunology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology
D000701:Analgesics, Opioid; D001572:Benzofurans; D016760:Proto-Oncogene Proteins c-fos; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D005557:Formaldehyde; D009270:Naloxone; C067110:enadoline