Vanilloid type 1 receptors (VR1) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin-induced dural dilation

Abstract

Capsaicin, the active substance in chilli peppers, activates the vanilloid type 1 receptor (VR1) rather than the vanilloid-like receptor (VRL1) in the trigeminal ganglion and nucleus of small and medium C- and Adelta-fibres. Capsaicin induces calcitonin gene-related peptide (CGRP) release when VR1 receptors are activated, and this can be reversed by both the VR1 receptor antagonist capsazepine and the CGRP blocker alphaCGRP8-37 in vitro. In this study we used intravital microscopy to look at the possible role of the VR1 receptor in the trigeminovascular system in producing dilation of dural blood vessels. Capsazepine (3 mg kg-1) was given to study the effect of the VR1 receptor in dural vessel dilation produced by either electrical stimulation, CGRP (1 microg x kg-1) or capsaicin (7 microg x kg-1) bolus injection. We also looked at the effect of the CGRP blocker alphaCGRP8-37 (300 microg x kg-1) on capsaicin-induced dilation so that we could see if the results found in vitro could also be found in vivo. Electrical stimulation of the dura mater produced a robust vasodilator response between 130 and 137% of baseline diameter that was no different across four repeat stimuli (F3,18=0.6, P=0.61). CGRP similarly produced a dilatation of 99-111% that was no different across four baseline infusions (F3,15=2.4, P=0.113). Capsaicin also produced a consistent dilation of between 112 and 120% of baseline across three injections (F2,10=0.6, P=0.567). Capsazepine did not inhibit the dilation brought about by either electrical stimulation or CGRP injection, while it was able to inhibit the dilation brought about by capsaicin (t5=3.4, P<0.05). AlphaCGRP8-37 also inhibited the capsaicin-induced dilation (t5=7.4, P<0.05) probably inhibiting the action of released CGRP at the CGRP receptor. The study demonstrates that capsaicin can repeatedly induce dural vessel dilation in vivo, presumably through inducing CGRP release from trigeminal sensory nerve fibres, while C-fibres may have been desensitised. The data imply that the VR1 receptor plays only a minor role in trigeminovascular-induced dural vessel dilation.

Figure 1

Effects of repeated capsaicin (up to 7 μg kg⁻¹) injection with capsazepine treatment (grey) on dural blood vessel diameter. Following control responses rats were injected capsazepine (1 and 3 mg kg⁻¹) and capsaicin injection repeated. ^*P<0.05 significance compared to the control response.

Figure 2

Effects of repeated capsaicin (7 μg kg⁻¹) injection with CGRP_8–37 (grey) on dural blood vessel diameter. Following control responses rats were injected with CGRP_8–37 (300 μg kg⁻¹) and capsaicin injection repeated. ^*P<0.05 significance compared to the control response. ^♯P<0.05 significance compared to the inhibitory response of CGRP_8–37.