Differential involvement of TRPV1 receptors at the central and peripheral nerves in CFA-induced mechanical and thermal hyperalgesia.
Transient receptor potential vanilloid 1 (TRPV1) antagonists are known to attenuate two typical symptoms of inflammatory hyperalgesia: thermal and mechanical. However, it is not clear whether the sites of participation of TRPV1 for each symptom are different. In this study, we clarified the difference between the site of TRPV1 involvement in both symptoms by analysing the anti-hyperalgesic activity of two kinds of TRPV1 antagonists given locally (i.e. intraplantarly and intrathecally) in rats with CFA (complete Freund's adjuvant)-induced inflammation. TRPV1 antagonists BCTC (N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide, 1-300 microg) and SB-366791 (N-(3-methoxyphenyl)-4-chlorocinnamide, 30-300 microg) administered intraplantarly in a dose-dependent manner inhibited CFA-induced thermal hyperalgesia. In addition, CFA-induced thermal hyperalgesia was significantly reversed by intrathecal administration of 1-100 microg of BCTC and SB-366791. While intraplantar BCTC (1-300 microg) and SB-366791 (30-300 microg) did not reverse CFA-induced mechanical hyperalgesia, 1-100 microg of intrathecally administered BCTC and SB-366791 dose-dependently reduced mechanical hyperalgesia. Regression analysis showed that a correlation exists between the inhibitory effects on thermal hyperalgesia and mechanical hyperalgesia after intrathecal administration (correlation factor = 0.6521), but not after intraplantar administration (correlation factor = 0.0215). These data suggest that TRPV1 in the peripheral endings of the primary afferents plays a key role in thermal hyperalgesia, but it makes only a minor contribution in CFA-induced mechanical hyperalgesia. Furthermore, it is suggested that the spinal TRPV1 is critical in the development of both types of hyperalgesia.
Kanai
Yoshihito
Y
Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. yoshihito.kanai@pfizer.com
Hara
Tomokazu
T
Imai
Aki
A
Sakakibara
Ayano
A
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy*; D007267:Injections; D007278:Injections, Spinal; D008297:Male; D009411:Nerve Endings / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000700:Analgesics; D000813:Anilides; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D011719:Pyrazines; D011725:Pyridines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D005620:Freund's Adjuvant