Further evidence for the interaction of μ- and δ-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

Abstract 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 (μ, δ, or κ) and their possible interactions, in the depressive effects of RB101 in inflammatory nociceptive conditions induced by intraplantar carrageenin (6 mg/150 μl of saline). We used β-funaltrexamine (β-FNA), naltrindole (NTI), and nor-binaltorphimine (BNI) as specific antagonists for μ-, δ- and κ-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