Modulation of ~-mediated antinociception by ~ agonists: characterization with antagonists

The functional interactions between supraspinal p, and 8 receptors were characterized in the mouse using p, receptor-selective antagonists. The effects of pretreatment with the p, opioid antagonists, /~-funaltrexamine (/'/-FNA) and naloxonazine on the modulation of morphine antinociception by the 8 agonists [D-PenZ,D-PenS]enkephalin (DPI)PE) and [D-AlaZ,MetS]enkephalinamide (DAMA) were studied. When co-administered in the same i.c.v. injection, a sub-antinociceptive dose of DPDPE consistently and significantly increased the antinociceptive potency of morphine in control animals, while a sub-effective dose of DAMA decreased morphine antinociception: both the respective increase and the decrease of morphine potency by DPDPE and DAMA had been previously shown to be blocked by ICI 174,864, a 8 antagonist. Pretreatment of mice with the non-equilibrium p. antagonist /'/-FNA 4 h prior to testing, a pretreatment which had no effect on i.c.v. DPDPE or DAMA antinociception, prevented the modulation of morphine antinociception by both DPDPE and DAMA. Pretreatment with the long acting pq antagonist naloxonazine, 24 h prior to testing, failed to affect the modulation of morphine antinociception by either DPDPE or DAMA: such a pretreatment had no effect on the antinociceptive effects of DPDPE or DAMA when given alone. These results provide further support for the concept of a functionally coupled p.-6 receptor complex which is sensitive to antagonism by fl-FNA, but not naloxonazine, and support the notion that subtypes of opioid p~ and 8 (i.e. complexed and non-complexed) receptors may exist.