A Peripheral Adrenoceptor-mediated Sympathetic Mechanism Can Transform Stress-induced Analgesia into Hyperalgesia

Background: Stress has paradoxical effects on pain, causing stress-induced analgesia but also exacerbating pain via poorly understood mechanisms. Adrenergic neurotransmission is integral in pathways that regulate the response to both pain and stress. Hyperalgesia is often associated with enhanced adrenergic sensitivity of primary afferents, but sympathetic nervous system outflow has not been demonstrated to exacerbate pain perception after stress. Methods: Rats or C57/BL6 wild-type mice treated with alpha-2 receptor antagonists or alpha-2A receptor knockout mice were exposed to ultrasonic noise stress or footshock stress and subsequently tested for hotplate paw withdrawal latencies. The sensory sensitivity of alpha-2A knockout mice to electrical and chemical stimuli was tested neurophysiologically and behaviorally. The effects of sympatholytic treatments were investigated. Results: Noise and footshock stressors induced thermal hyperalgesia in rats pretreated systemically with alpha-2 antagonists. Wild-type mice pretreated with alpha-2 antagonists and alpha-2A knockout mice also exhibited thermal hyperalgesia induced by noise stress. Local spinal or intraplantar injection of an alpha-2 antagonist counteracted stress-induced analgesia without causing hyperalgesia. The alpha-2A knockout mice had decreased thresholds for peripheral sensitization with sulprostone and for windup of the dorsal horn neuronal response to repetitive electrical stimuli. Stress-induced hyperalgesia was abolished and the sensitization was attenuated by sympathectomy or systemic administration of an alpha-1-adrenergic antagonist. Conclusions: Sympathetic postganglionic nerves can enhance pain sensation via a peripheral alpha-1-adrenoceptor mechanism when sympathetic outflow is disinhibited. The net effect of stress on pain sensation reflects a balance between descending spinal inhibition and sympathetic outflow that can shift toward pain facilitation when central and peripheral alpha-2-adrenoceptor inhibitory mechanisms are attenuated.