title: Spinal NK1 receptors contribute to the increased excitability of the nociceptive flexor reflex during persistent peripheral inflammation.
abstract: Hyperalgesia is a characteristic of inflammation and is mediated, in part, by an increase in the excitability of spinal neurons. Although substance P does not appear to mediate fast synaptic events that underlie nociception in the spinal cord, it may contribute to the hyperalgesia and increased excitability of spinal neurons during inflammation induced by complete Freund's adjuvant. We examined the role of endogenous substance P in changes in the excitability of spinal neurons during adjuvant-induced, peripheral inflammation by determining the effect of a selective NK1 receptor antagonist (RP67580) on the nociceptive flexor reflex in adult rats. Experiments were conducted 2 or 3 days after injection of adjuvant. Animals exhibited moderate thermal hyperalgesia at this time. The flexor reflex was evoked by electrical stimulation of the sural nerve and was recorded in the ipsilateral hamstring muscles. The flexor reflex ipsilateral to the inflamed hindpaw was enhanced approximately two-fold compared to the flexor reflex evoked in untreated animals as determined by the number of potentials and the duration of the reflex. The enhanced reflex in adjuvant-treated animals was most likely due to an increase in the excitability of spinal interneurons because short-latency activity in the hamstring muscles did not differ between untreated animals and adjuvant-treated animals following electrical stimulation of the L5 dorsal root or the nerve innervating the muscle with a stimulus that was 1.3-1.5 times the threshold for excitation of A-fibers. Intrathecal administration of RP67580 (2.3 and 6.8 nmol) attenuated the flexor reflex evoked in adjuvant-treated animals, but had no effect in untreated animals. Intravenous or intraplantar injection of RP67580 (6.8 nmol) did not affect the flexor reflex in adjuvant-treated animals indicating a spinal action of the drug following intrathecal administration. RP68651, the enantiomer of RP67580, was without effect at doses up to 6.8 nmol, indicating that the effects of comparable doses of RP67580 were due to an action of the drug at NK1 receptors. However, intrathecal administration of 23 nmol of both drugs attenuated the reflex in adjuvant-treated and control animals indicating that effects of RP67580 at this dose were not mediated entirely by its action at NK1 receptors. Overall, these data suggest that endogenous substance P has a role in the increased excitability of spinal interneurons observed during persistent inflammation and support the hypothesis that substance P released in the spinal cord contributes to the hyperalgesia that accompanies adjuvant-induced persistent, peripheral inflammation.
authors.affiliation: Department of Cell Biology and Neuroanatomy, University of Minnesota, Minneapolis 55455, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Parsons
authors.forename: C N
authors.initials: CN
authors.lastname: Honda
authors.forename: Y P
authors.initials: YP
authors.lastname: Jia
authors.forename: D
authors.initials: D
authors.lastname: Budai
authors.forename: X J
authors.initials: XJ
authors.lastname: Xu
authors.forename: Z
authors.initials: Z
authors.lastname: Wiesenfeld-Hallin
authors.forename: V S
authors.initials: VS
authors.lastname: Seybold
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002908:Chronic Disease; D004558:Electric Stimulation; D004576:Electromyography; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009443:Neuritis / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology*; D012026:Reflex, Stretch / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013497:Sural Nerve / Q000502:physiology
chemical_list: D018040:Receptors, Neurokinin-1