The antihyperalgesic effects of TRPV1 receptor antagonists have been increasingly documented in animal models of both neuropathic and inflammatory pain. Although capsazepine has traditionally been used as an antagonist of these channels, its use is potentially problematic due to a limited selectivity and modality-specific antagonism. We have recently described the properties of a novel inhibitor of both recombinant and native TRPV1 channels SB-366791, which lacks many of the experimental liabilities of capsazepine, (Gunthorpe et al. 2004).

In the present study, we examined the effects of SB-366791 on glutamatergic synaptic transmission in substantia gelatinosa neurones within spinal cord slices prepared from male Lister-hooded rats, aged 17-26 days. Furthermore, we compared data from control rats and identical animals that have undergone a prior 24 h period of peripheral inflammation induced by an subcutaneous intraplantar injection of Freund’s complete adjuvant (FCA) to the left hind paw. Following humane killing, 400 µm thick spinal cord slices were prepared from a region approximately encompassing L4-L6. Spontaneous excitatory post-synaptic currents (sEPSC) were then measured in whole cell voltage-clamp recordings of substantia gelatinosa neurones clamped at -70 mV.

In control animals, SB-366791 (30 µM) affected neither the amplitude (94.1 ± 2.4% of control, n = 9) nor frequency (99.4 ± 3.4% of control, n = 9) of sEPSCs. However, in 5/10 of FCA-inflamed animals, the addition of SB-366791 decreased sEPSC frequency to 66.3 ± 7.9% of its predrug level but produced no significant effect on sEPSC amplitude (92.2 ± 3.6% of control). Furthermore, the frequency of miniature glutamatergic EPSC (mEPSC), isolated in 1 µM TTX, from slices taken from FCA-treated animals was reduced by 30 µM SB-366791 in 6/7 animals (63.1 ± 4.2% of control values), without any corresponding change in the amplitude (95.7 ± 3.8% of control) of the mEPSC population.

These results suggest a presynaptic location for TRPV1 receptors on the terminals of glutamatergic neurones. We hypothesise that during peripheral inflammation TRPV1 receptors in sensory terminals become spontaneously active, resulting in an increased vesicular release of glutamate. These results provide new functional evidence for the involvement of TRPV1 in chronic inflammatory pain and provide a cellular basis for the antihyperalgesic effects of TRPV1 receptor antagonists.