Meisner Jason G, Waldron James B, Sawynok Jana
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
J Pain. 2007 Jul;8(7):556-62. doi: 10.1016/j.jpain.2007.02.434. Epub 2007 May 23.
In the present study, the adrenergic receptor (AR) subtype mediating adrenergic augmentation of P2X(3) 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 alphabeta-methyleneATP (ligand for P2X3/P2X2/3 receptors) into the plantar hind paw produced few pain behaviors when given alone in this strain of rats; combination with adrenaline (alpha1- and alpha2-AR agonist) and phenylephrine (alpha1-AR agonist) but not clonidine or UK 14,304 (alpha2-AR agonists) increased flinching behaviors. Flinching produced by noradrenaline (NA)/alphabeta-methyleneATP was suppressed by low doses of prazosin (alpha1-AR antagonist), and this reduction was selective compared with yohimbine (alpha2-AR antagonist). Prazosin also reduced flinching produced by phenylephrine/alphabeta-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 alphabeta-methyleneATP. Terazosin (another alpha1-AR antagonist) inhibited hyperalgesia produced by NA/alphabeta-methyleneATP. These results provide evidence for alpha1-AR involvement in adrenergic augmentation of P2X3/P2X2/3 receptor-mediated responses on sensory nerve endings in the uninjured state in Sprague Dawley rats.
This study indicates the alpha1-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.
在本研究中，通过在未受伤状态的Sprague Dawley大鼠中使用选择性肾上腺素能受体（AR）激动剂和拮抗剂，研究了介导肾上腺素能增强感觉神经末梢上P2X(3)受体介导的伤害性反应的AR亚型。在该品系大鼠中，单独向足底后爪局部注射αβ-亚甲基ATP（P2X3/P2X2/3受体的配体）时几乎不产生疼痛行为；与肾上腺素（α1和α2-AR激动剂）和去氧肾上腺素（α1-AR激动剂）联合使用会增加退缩行为，但与可乐定或UK 14,304（α2-AR激动剂）联合使用则不会。去甲肾上腺素（NA）/αβ-亚甲基ATP引起的退缩行为可被低剂量的哌唑嗪（α1-AR拮抗剂）抑制；与育亨宾（α2-AR拮抗剂）相比，这种降低具有选择性。哌唑嗪还减少了去氧肾上腺素/αβ-亚甲基ATP引起的退缩行为。通过热阈值测定，肾上腺素和去氧肾上腺素而非可乐定或UK 14,304模拟了NA增强αβ-亚甲基ATP引起的热阈值降低的作用。特拉唑嗪（另一种α1-AR拮抗剂）抑制了NA/αβ-亚甲基ATP引起的痛觉过敏。这些结果为α1-AR参与Sprague Dawley大鼠未受伤状态下感觉神经末梢上P2X3/P2X2/3受体介导的反应的肾上腺素能增强提供了证据。
本研究表明，α1-肾上腺素能受体亚型在外周介导嘌呤能P2X3受体（对ATP有反应）对感觉神经激活的肾上腺素能增强作用。这些观察结果可能与交感神经影响感觉神经的慢性疼痛状况相关。
