α₁-Adrenergic Receptors Augment P2X₃ Receptor-Mediated Nociceptive Responses in the Uninjured State

In the present study, the adrenergic receptor (AR) subtype mediating adrenergic augmentation of P2X₃ receptor-mediated nociceptive responses on sensory nerve endings was examined by using selective AR receptor agonists and antagonists in Sprague Dawley rats in the uninjured state. Local administration of αβ-methyleneATP (ligand for P2X₃/P2X_2/3 receptors) into the plantar hind paw produced few pain behaviors when given alone in this strain of rats; combination with adrenaline (α1- and α2-AR agonist) and phenylephrine (α1-AR agonist) but not clonidine or UK 14,304 (α2-AR agonists) increased flinching behaviors. Flinching produced by noradrenaline (NA)/αβ-methyleneATP was suppressed by low doses of prazosin (α1-AR antagonist), and this reduction was selective compared with yohimbine (α2-AR antagonist). Prazosin also reduced flinching produced by phenylephrine/αβ-methyleneATP. Using thermal threshold determinations, adrenaline and phenylephrine but not clonidine or UK 14,304, mimicked the action of NA in augmenting reductions in thermal thresholds produced by αβ-methyleneATP. Terazosin (another α1-AR antagonist) inhibited hyperalgesia produced by NA/αβ-methyleneATP. These results provide evidence for α1-AR involvement in adrenergic augmentation of P2X₃/P2X_2/3 receptor-mediated responses on sensory nerve endings in the uninjured state in Sprague Dawley rats. Perspective: This study indicates the α1-adrenergic receptor subtype mediates adrenergic augmentation of the activation of sensory nerves by purinergic P2X₃ receptors (respond to ATP) in the periphery. Observations are potentially relevant to chronic pain conditions in which sympathetic nerves influence sensory nerves.