Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats.
Vanilloid receptor 1 (TRPV1) antagonists are known to attenuate the neuropathic pain symptoms in peripheral nerve injury models, but the mechanism(s) of their effect remains unclear. At the same time, the role of spinal TRPV1 in pain transduction system has not been fully understood. In this study, the role of spinal TRPV1 in mechanical allodynia in rat chronic constriction injury (CCI) model was investigated. Intrathecal administration of a selective TRPV1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbox-amide (BCTC) significantly attenuated mechanical allodynia in CCI rats at 100 and 300 nmol. In vitro, BCTC inhibited capsaicin (300 nM)-induced releases of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and substance P-like immunoreactivity (SP-LI) from the rat spinal cord slice preparations with IC(50)s of 37.0 and 36.0 nM, respectively, confirming that BCTC potently inhibits TRPV1 function in the rat spinal cord. TRPV1 expression levels in the spinal cord following CCI were quantified in by Western blot analysis. TRPV1 protein levels were significantly increased in the ipsilateral side of the lumbar spinal cord at 7 and 14 days following CCI surgery, but not in the contralateral side. Furthermore, capsaicin (300 nM)-evoked release of CGRP-LI was significantly higher in the ipsilateral spinal cord of CCI rats (14 days after surgery) than that of sham-operated rats. These findings suggest that an increased sensitization of the spinal TRPV1 through its up-regulation is involved in the development and/or maintenance of mechanical allodynia in rat CCI model.
Pfizer Global Research and Development, Efficacy Pharmacology I, 5-2, Taketoyo, Aichi 470-2393, Japan. yoshito.kanai@japan.pfizer.com
Yoshihito
Y
Kanai
Etsuko
E
Nakazato
Akiyoshi
A
Fujiuchi
Tomokazu
T
Hara
Aki
A
Imai
D000818:Animals; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009479:Neuropeptides / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*
C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011719:Pyrazines; D011725:Pyridines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin