Vol. 291, Issue 3, 1028-1037, December 1999

Neural and Endocrine Mechanisms Mediating Noxious Stimulus-Induced Inhibition of Bradykinin Plasma Extravasation in the Rat¹

Frederick Jia-Pei Miao and Jon D. Levine

Departments of Medicine (F.J.-P.M., J.D.L.), Anatomy (J.D.L.), and Oral and Maxillofacial Surgery (J.D.L.) and National Institutes of Health Pain Center (F.J.-P.M., J.D.L.), University of California at San Francisco, Schools of Medicine and Dentistry, San Francisco, California

We studied the mechanisms by which activation of primary afferent nociceptors inhibits bradykinin-induced plasma extravasation in the rat. First, capsaicin, administered into the plantar surface of the hindpaw, dose-dependently inhibited bradykinin-induced plasma extravasation in the knee joint, a site distant from the noxious stimulus. The inhibitory effect of capsaicin was markedly attenuated after T₁₂/L₁ spinal transection combined with lumbar preganglionic sympathectomy, which interrupts ascending spinal tracts to rostral sites and to spinal sympathetic and sympathoadrenal outflow. Second, interruption of the sympathetics (cutting the L_1-3 white rami) or surgical adrenal denervation significantly attenuated capsaicin-induced inhibition of bradykinin-induced plasma extravasation. Interruption of the sympathoadrenal pathway produced the largest attenuation. Lesioning of the hypothalamic-pituitary-adrenal axis did not affect the inhibitory action of capsaicin. Third, intra-articular perfusion with phentolamine (10⁵ M, an -adrenoceptor antagonist), propranolol (10⁵ M, a -adrenoceptor antagonist), and naloxone (10⁵ M, an opioidergic receptor antagonist) each attenuated the inhibitory action of capsaicin. Propranolol and naloxone produced the largest attenuation. Blocking glucocorticoid receptors (RU-38,486, 30 mg/kg s.c.) did not affect the inhibitory action of intraplantar capsaicin. Fourth, the magnitude of the attenuation of capsaicin-induced inhibition of bradykinin-induced plasma extravasation after a combined treatment of surgical lumbar sympathetic decentralization with intra-articular phentolamine or surgical adrenal denervation with intra-articular propranolol or naloxone was similar to each of the surgical or pharmacological treatments of the same axis alone. These results support the suggestion that two neural/endocrine circuits, sympathoadrenal and sympathetic, account for most, if not all, of nociceptor activity-induced inhibition of bradykinin-induced plasma extravasation produced by capsaicin.