Proceedings of The Physiological Society
University of Cambridge (2008) Proc Physiol Soc 11, PC109
Role of Transient Receptor Potential Vanilloid 1 receptors in C- vs Aδ-fibre-evoked spinal nociception in naïve rats and in a model of post-operative pain
S. Koutsikou1, E. Davies1, A. Timperley1, K. Patel1, R. Apps1, J. Palecek2, B. Lumb1
1. Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom. 2. Functional Morphology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Transient Receptor Potential Vanilloid 1 (TRPV1) is a cation channel gated by noxious heat, H+ ions and capsaicin. TRPV1 is sensitised and upregulated in inflammation, and contributes to the development and maintenance of chronic pain. TRPV1 receptors are synthesised in the cell bodies of C-fibre primary afferents, and transported to both spinal and peripheral terminals. Much is known of their role in the periphery but less of their role at central terminals. The aim of this in vivo study was to investigate the effects of spinal TRPV1 receptor antagonism on the processing of C- vs Aδ-fibre-evoked spinal nociception; and to subsequently investigate the contribution of spinal TRPV1 receptors to central sensitisation in a rat model of post-operative pain. All experiments were carried out on male Wistar rats. Anaesthesia was induced by inhalation of halothane (2-3% in O2) and maintained using constant intravenous alfaxalone (16-30mg.kg-1hr-1). A heating lamp was evenly placed on the dorsal aspect of the hindpaw. Slow (1.7-2.5°Cs-1) and fast (6.5-7.5°Cs-1) surface heating rates were used to preferentially activate C- and Aδ-nociceptors respectively (McMullan et al., 2004). Withdrawal thresholds to noxious heating were recorded as EMG activity from the biceps femoris before and after intrathecal administration of the TRPV1 antagonist SB-366791 (Gunthorpe et al., 2004; 10μl, 100µM; n=3) or vehicle solution (n=1). For the post-operative pain model, rats were anaesthetised by inhalation of isoflurane (2-3% in O2) and a 1cm longitudinal incision was made through skin, fascia and muscle of the plantar hindpaw (Brennan et al., 1996). 24 hours post-surgery animals (n=3) were tested for the effects of spinal TRPV1 antagonism as described above. In naïve rats, SB-366791 administration significantly increased (P<0.05; Kruskal-Wallis test) withdrawal thresholds to slow but not fast rates of heating. In the model of post-operative pain SB-366791 increased withdrawal thresholds to both slow and fast rates. Comparison of the change in EMG threshold from pre-drug baseline between naïve and surgical model rats reveals a greater effect of the antagonist after surgical incision for both C- and Aδ-fibre activation. These results provide novel evidence that TRPV1 receptors in the spinal cord play a role in the central processing of C- but not Aδ-fibre nociceptive inputs in naïve rats. In the post-operative model, the augmented effect of SB-366791 on C- and Aδ-nociceptive processing suggests that post-incision, there is a sensitisation or upregulation of spinal TRPV1 receptors in both C- and Aδ-fibres. This provides evidence that spinal TRPV1 receptors play a role in central sensitisation in a model of post-operative pain and, as such, may prove a novel target for analgesic drugs.
Where applicable, experiments conform with Society ethical requirements