The α2aAdrenergic Receptor Subtype Mediates Spinal Analgesia Evoked by α2Agonists and Is Necessary for Spinal Adrenergic–Opioid Synergy

Abstract

Agonists acting at α 2 adrenergic and opioid receptors have analgesic properties and act synergistically when co-administered in the spinal cord; this synergy may also contribute to the potency and efficacy of spinally administered morphine. The lack of subtype-selective pharmacological agents has previously impeded the definition of the adrenergic receptor subtype(s) mediating these effects. We therefore exploited a genetically modified mouse line expressing a point mutation (D79N) in the α 2a adrenergic receptor (α 2a AR) to investigate the role of the α 2a AR in α 2 agonist-evoked analgesia and adrenergic–opioid synergy. In the tail-flick test, intrathecal administration of UK 14,304, a nonsubtype-selective α 2 AR agonist, had no analgesic effect in D79N mice, whereas the analgesic potency of morphine (intrathecal)in this assay was not affected by the mutation. The mutation also decreased α 2-agonist-mediated spinal analgesia and blocked the synergy seen in wild-type mice with both the δ-opioid agonist deltorphin II and the μ-opioid agonist [d-ALA 2,N-Me-Phe 4,Gly-ol 5]-Enkephalin (DAMGO) in the substance P behavioral test. In addition, the potency of spinally administered morphine was decreased in this test, suggesting that activation of descending noradrenergic systems impinging on the α 2a AR contributes to morphine-induced spinal inhibition in this model. These results demonstrate that the α 2a AR subtype is the primary mediator of α 2 adrenergic spinal analgesia and is necessary for analgesic synergy with opioids. Thus, combination therapies targeting the α 2a AR and opioid receptors may prove useful in maximizing the analgesic efficacy of opioids while decreasing total dose requirements.