Further evidence for the interaction of mu- and delta-opioid receptors in the antinociceptive effects of the dual inhibitor of enkephalin catabolism, RB101(S). A spinal c-Fos protein study in the rat under carrageenin inflammation.
We have previously shown that RB101, a dual inhibitor of enkephalin-degrading enzymes, decreased carrageenin-evoked c-Fos protein expression at the spinal cord level in awake rats. Moreover, we have also shown that c-Fos expression is a useful marker of the possible direct or indirect interactions between neural pathways, such as opioid and cholecystokinin systems. We now investigated the respective roles of the three main types of opioid receptors (mu, delta, or kappa) and their possible interactions, in the depressive effects of RB101 in inflammatory nociceptive conditions induced by intraplantar carrageenin (6 mg/150 microl of saline). We used beta-funaltrexamine (beta-FNA), naltrindole (NTI), and nor-binaltorphimine (BNI) as specific antagonists for mu, delta- and kappa-opioid receptors, respectively. c-Fos protein-immunoreactivity (c-Fos-IR) was evaluated as the number of c-Fos-IR nuclei in the lumbar spinal cord 90 min after carrageenin. c-Fos-IR nuclei were preferentially located in the superficial (I-II) and deep (V-VI) laminae of segments L4-L5 (areas containing numerous neurons responding exclusively, or not, to nociceptive stimuli). RB101(S) (30 mg/kg, i.v.) significantly reduced the total number of carrageenin-evoked c-Fos-IR nuclei (30% reduction, P<0.01). This effect was completely blocked by beta-FNA (10 mg/kg, i.v.), or NTI (1 mg/kg, i.v.). In contrast, BNI (2.5 mg/kg, i.v.) did not reverse the reducing effects of RB101(S) on carrageenin-evoked c-Fos protein expression. These results suggest that functional interactions occur between mu- and delta-opioid receptors in enkephalin-induced antinociceptive effects.
Le Guen
Stéphanie
S
Laboratoire de Pharmacochimie Moléculaire et Structurale, INSERM U266-CNRS FRE2463, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France. leguen@pharmacie.univ-paris5.fr
Catheline
Gwénaëlle
G
Fournié-Zaluski
Marie Claude
MC
Roques
Bernard Pierre
BP
Besson
Jean Marie
JM
Buritova
Jaroslava
J
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan; D004220:Disulfides / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004745:Enkephalins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D000700:Analgesics; D004220:Disulfides; D004745:Enkephalins; D016760:Proto-Oncogene Proteins c-fos; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C074024:RB 101; D010649:Phenylalanine; D002351:Carrageenan