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J Neurophysiol 95: 18-25, 2006. First published September 14, 2005; doi:10.1152/jn.00560.2005
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Systemic and Site-Specific Effects of A-425619, a Selective TRPV1 Receptor Antagonist, on Wide Dynamic Range Neurons in CFA-Treated and Uninjured Rats

Steve McGaraughty, Katharine L. Chu, Connie R. Faltynek and Michael F. Jarvis

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Submitted 27 May 2005; accepted in final form 10 September 2005

Systemic administration of A-425619, a potent and selective TRPV1 receptor antagonist that does not readily enter the CNS, produces antinociception in several rat models of pathological nociception, including complete Freund's adjuvant (CFA)-induced thermal hyperalgesia. To further understand the peripheral mechanisms of TRPV1-related antinociception, we examined the effects of systemic and site-specific injections of A-425619 on evoked and spontaneous firing of spinal wide dynamic range (WDR) neurons in uninjured rats and rats with peripheral inflammation (CFA; 48 h). In uninjured rats, capsaicin-evoked (1 µg) WDR activity was completely blocked by intraplantar administration of A-425619 (3–100 nmol). Systemic injection of A-425619 (3–30 µmol/kg, iv) reduced WDR responses to thermal stimulation in both CFA-inflamed (47°C) and uninjured (52°C) rats. However, the efficacy of A-425619 to attenuate thermal-evoked WDR activity was significantly greater (P < 0.01) in CFA-treated rats. Both intradorsal root ganglion (DRG; L5; 20 nmol) and intraplantar (30–300 nmol) injection of A-425619 reduced WDR responses to thermal stimulation. While the effectiveness of A-425619 was similar between CFA-inflamed and uninjured rats after intraplantar injection, the effects of A-425619 after intra-DRG injection were enhanced in the inflamed rats (compared with the uninjured rats). Spontaneous WDR discharges were unaltered by systemic or site-specific injections of A-425619. Thus noxious thermal stimulation triggers the transmission of TRPV1-related signals to spinal WDR neurons in both inflamed and uninjured animals. The apparent increase in TRPV1 signaling to WDR neurons after injury may be the result of changes to the distribution/sensitization of peripheral TRPV1 receptors.

Address for reprint requests and other correspondence: S. McGaraughty, Neuroscience Res., Abbott Laboratories, R4PM, AP9-1, 100 Abbott Park Rd., Abbott Park, IL 60064-6118 (E-mail: Steve.P.McGaraughty{at}abbott.com)




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