G-protein activation by neurokinin-1 receptors is dynamically regulated during persistent nociception.
Previous work has demonstrated that persistent nociception evokes increased neurokinin-1 receptor (NK-1) gene expression in the spinal cord dorsal horn of the rat within 2 h but has failed to elucidate the relationship between increased NK-1 gene expression at later time points and functional regulation of NK-1 receptor signaling. This study was undertaken to assess changes in NK-1 receptor mRNA levels in models of persistent inflammatory hyperalgesia and to relate them to changes in the functional coupling of NK-1 receptors to G-protein activity in the dorsal horn of the rat. Thus, unilateral intraplantar formalin or complete Freund's adjuvant was used to alter mechanical and thermal withdrawal thresholds in the inflamed paw. One to 96 h later, NK-1 receptor mRNA levels were quantified using solution hybridization-nuclease protection assays. Formalin-evoked inflammation produced a 2-fold unilateral increase in NK-1 receptor mRNA levels apparent from 2 to 96 h postinjection. Histological sections of the lumbar cord from similarly treated rats were used to generate concentration-response curves using GTPgammaS35 functional binding assays stimulated by an NK-1 selective agonist. Results showed that formalin evoked a transient, bilateral decrease in the maximal functional response to 35% of control in the treated side at 24 h postinjection and as much as a 10-fold leftward shift in the EC50 of the agonist at 12 to 96 h postinjection. These results provide novel evidence that peripheral nociceptive activation promotes a central mechanism of hyperalgesia through increased functional sensitivity of NK-1 receptors in the spinal cord dorsal horn.
University of Kansas Medical Center, Department of Pharmacology, Toxicology, and Therapeutics, Kansas City, KS 66160-7417, USA.
Michelle K
MK
Winter
Kenneth E
KE
McCarson
D000818:Animals; D005557:Formaldehyde / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*
D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D005557:Formaldehyde; D005620:Freund's Adjuvant; D019204:GTP-Binding Proteins