Peripherally located TRPV1 receptors are not important in TNFalpha-induced mechanical hyperalgesia

Fiona Russell, Susan Brain. King's College London, London, United Kingdom.

Mechanical hyperalgesia is the heightened sensitivity to pressure and occurs during inflammation. This group has found that TNFalpha induces a bilateral TRPV1-dependent thermal hyperalgesia (Russell et al., 2005) but, as yet, the role for TRPV1 in TNFalpha-induced mechanical hyperalgesia is unknown. Therefore, the aim of this study was to investigate if TRPV1 is important in TNFalpha-induced mechanical hyperalgesia by utilising the selective TRPV1 antagonist, SB-366791.

Female CD1 mice (25-30g) were pre-treated with either SB-366791 (0.5mg/kg i.p. 30 min pre-experiment) or vehicle (1% DMSO saline). Intraplantar injections (i.pl.) of TNFalpha (10pmol/50microl) and Tyrode (as vehicle, contralateral paw, 50microl). Mechanical hyperalgesic thresholds were determined using a dynamic plantar aesthesiometer (Ugo Baslie, Italy) before and 4h after injection. Mean of triplicate values was taken as paw withdrawal threshold (p.w.t., in g). In separate experiments, SB-366791 (0.3nmol, previously shown to inhibit TNFalpha-induced thermal hyperalgesia by 66 ± 20%) was co-injected with TNFalpha (10pmol) i.pl. (total volume 50microl), whilst contralateral paw was injected with Tyrode plus corresponding amounts of SB-366791 vehicle (1% DMSO saline).Results are expressed as mean ± s.e.m. and statistical analysis performed using paired t-test.

Systemic treatment with SB-366791 blocked the reduction in p.w.t. seen at 4h in both paws of vehicle-treated mice (Figure 1A). However, local injection of SB-366791 with TNFalpha was unable to block the bilateral mechanical hyperalgesia at 4h (Figure 1B)

Figure 1. Mechanical hyperalgesic thresholds before and 4h post-injection of TNFalpha (10pmol) in A) vehicle and SB-366791 treated mice (0.5mg/kg i.p.) and B) mice co-injected with TNFalpha plus SB-366791 (0.3nmol, ipsilateral paw) amd Tyrode plus 1% DMSO saline (contralateral paw). n=4-8, *p<0.05 compared to baseline value in same paw.

Systemic treatment with the TRPV1 antagonist blocked TNFalpha-induced mechanical hyperalgesia implying a role for TRPV1 in this pain hypersensitivity state. However, local injections of the antagonist could not block the mechanical hyperalgesia suggesting that peripherally located TRPV1 receptors are not important in the development of TNFalpha-induced mechanical hyperalgesia.

Russell,F.A. et al., (2005).Proceedings of the British Pharmacological Society at: http://www.pa2online.org/abstracts/Vol3Issue2abst115P.pdf.

Funded by BBSRC/Pfizer CASE.