Proceedings of The Physiological Society
Cardiff University (2009) Proc Physiol Soc 17, C13
Neurons in the rostral ventromedial medulla (RVM) that possess the NK-1 receptor contribute to descending facilitation of spinal nociceptive transmission
S. G. Khasabov1, D. A. Simone1
1. Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, Minnesota, United States.
Activation of neurokinin-1 receptors (NK-1R) in the spinal cord by substance P (SP) released from nociceptive afferent fibers contributes to central sensitization and hyperalgesia. Neurons possessing NK-1R are also found in the RVM, an area of the brainstem that gives rise to descending modulation of nociceptive transmission in the spinal cord. It has been suggested that RVM neurons with NK-1R contribute to descending facilitation of pain. We therefore investigated the effects of ablation of RVM neurons with NK-1R on acute pain, development of hyperalgesia, and sensitization of spinal neurons. To eliminate NK-1R expressing neurons, the ribosomal toxin Saporin (SAP) conjugated to the SP stable analog Sar9,Met(O2)11-Substance P (SSP-SAP; 1 μM/0.5 μl) or Blank-SAP (control) was injected into the RVM of Sprague Dawley rats under i.p. ketamine anesthesia. At 14-28 days after injection, SSP-SAP reduced the number of NK-1R positive neurons in the RVM (0.3% ± 0.16% of all neurons) compared to Blank-SAP (7.1% ± 1.05%) and naïve (6.8% ± 0.57%) rats (one-way ANOVA, p<0.001). SSP-SAP did not alter the frequency of paw withdrawal, evoked by a 15g von Fray monofilament, or paw withdrawal threshold. However, SSP-SAP produced a 50% decrease in the duration of nocifensive behavior following intraplantar injection of capsaicin (p<0.001, t-test) and decreased the magnitude of mechanical hyperalgesia. To determine whether activation of NK-1R in the RVM are involved in sensitization of nociceptive neurons in the spinal cord, we examined the effects of injection of the NK-1R antagonist L-733,060 (1.5 pmol/0.5µl) or vehicle into the RVM on electrophysiological responses of spinal neurons in rats anesthetized with i.v. Nembutal. The NK-1R antagonist reduced responses evoked by capsaicin and the ensuing sensitization to mechanical stimuli (p<0.05; one- and two-way repeated measures AVOVA). These results were consistent with our previous behavioral studies in which injection of L-733,060 into the RVM decreased the duration of nocifensive behaviors and mechanical hyperalgesia produced by capsaicin. We also determined whether activation of NK-1R in the RVM produced hyperalgesia. Injection of the NK-1R agonist Sar9,Met(O2)11-Substance P (SSP) (0.1-10 nmol/0.5 μl) into the RVM reduced paw withdrawal threshold at doses of 3, 5, and 10 nmol (p<0.05; two-way repeated measures AVOVA). Withdrawal thresholds decreased by approximately 5-6 g. We conclude that neurons in the RVM that possess NK-1 receptors have a unique role in descending facilitation of spinal nociceptive transmission and hyperalgesia evoked by capsaicin. These neurons in the RVM do not appear to modulate acute pain.
Where applicable, experiments conform with Society ethical requirements