Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors.

摘要: Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord show a clinically beneficial synergistic interaction co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting complex between two systems. The α2A-AR subtype is necessary for adrenergic analgesia synergy with opioids most agonist combinations. Therefore, we investigated whether antinociception opioid-adrenergic were under allosteric control of α2A-AR. Drugs intrathecally wild type (WT) α2A-knock-out (KO) mice was measured using hot water tail immersion or substance P behavioral assays. clonidine less effective α2A-KO both absence resulted 10-70-fold increases antinociceptive potency morphine DeltII. In contrast, neither nor DeltII synergized mice, indicating that α2AAR has positive negative modulatory effects on antinociception. Depletion descending terminals 6-OHDA significant decrease efficacy WT but not endogenous norepinephrine acts through to facilitate Based these findings, propose model whereby ligand-occupied versus ligand-free produce distinct patterns modulation receptor activation. this model, agonist-occupied α2A-ARs potentiate analgesia, while non-occupied analgesia. Exploiting such interactions receptors could lead development better pharmacological treatments pain management.