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Agonists acting at α2 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 α2a adrenergic receptor (α2aAR) to investigate the role of the α2aAR in α2 agonist-evoked analgesia and adrenergic–opioid synergy. In the tail-flick test, intrathecal administration of UK 14,304, a nonsubtype-selective α2AR 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 α2-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-ALA2,N-Me-Phe4,Gly-ol5]-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 α2aAR contributes to morphine-induced spinal inhibition in this model. These results demonstrate that the α2aAR subtype is the primary mediator of α2 adrenergic spinal analgesia and is necessary for analgesic synergy with opioids. Thus, combination therapies targeting the α2aAR and opioid receptors may prove useful in maximizing the analgesic efficacy of opioids while decreasing total dose requirements.

the journal of neuroscience/the journal of neuroscience

The α<sub>2a</sub>Adrenergic Receptor Subtype Mediates Spinal Analgesia Evoked by α<sub>2</sub>Agonists and Is Necessary for Spinal Adrenergic–Opioid Synergy

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

The α_2aAdrenergic Receptor Subtype Mediates Spinal Analgesia Evoked by α₂Agonists and Is Necessary for Spinal Adrenergic–Opioid Synergy