μ/δ Cooperativity and opposing κ-opioid effects in nucleus accumbens-mediated antinociception in the rat

We previously demonstrated that noxious peripheral stimulation (e.g. subdermal capsaicin injection in the hind paw) produces antinociception that is mediated by opioid receptors in nucleus accumbens. The current study used the trigeminal jaw-opening nociceptive reflex responses in the rat to assess the role of intra-accumbens μ-, δ- and κ-opioid receptors in the antinociceptive effect of noxious stimulation and intra-accumbens opioid agonism. Whilst intra-accumbens injection of either the μ-receptor-selective antagonist Cys²,Tyr³,Orn⁵,Pen⁷amide (CTOP) or the δ-receptor-selective antagonist naltrindole blocked capsaicin-induced antinociception, neither the selective μ-agonist [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO; 150 or 300 ng) nor the selective δ-agonist D-Pen^2,5-enkephalin (DPDPE; 150 or 300 ng) alone induced antinociception. Simultaneous injection of DAMGO and DPDPE (150 ng each), however, produced significant antinociception. Capsaicin-induced antinociception was not blocked by the selective κ-receptor antagonist nor-binaltorphimine, but was blocked by the κ-agonist U69,593. U69,593 also antagonized the antinociceptive effect of the DAMGO/DPDPE combination. Thus, in nucleus accumbens, μ- and δ- but not κ-opioid receptors contributed to capsaicin-induced antinociception; selective activation of individual receptor subtypes was insufficient, but coactivation of μ- and δ-opioid receptors induced antinociception, and κ-receptors appeared to play an antianalgesic role in nucleus accumbens.