Sumatriptan Inhibits TRPV1 Channels in Trigeminal Neurons

Abstract

Objective To understand a possible role for transient potential receptor vanilloid 1 (TRPV1) ion channels in sumatriptan relief of pain mediated by trigeminal nociceptors. Background TRPV1 channels are expressed in small nociceptive sensory neurons. In dorsal root ganglia (DRG), TRPV1-containing nociceptors mediate certain types of inflammatory pain. Neurogenic inflammation of cerebral dura and blood vessels in the trigeminal nociceptive system is thought to be important in migraine pain, but the ion channels important in transducing migraine pain are not known. Sumatriptan is an agent effective in treatment of migraine and cluster headache. We hypothesized that sumatriptan might modulate activity of TRPV1 channels found in the trigeminal nociceptive system. Methods We used immunohistochemistry to detect the presence of TRPV1 channel protein, whole cell recording in acutely dissociated trigeminal ganglia (TG) to detect functionality of TRPV1 channels, and whole cell recording in trigeminal nucleus caudalis (TNC) to detect effects on release of neurotransmitters from trigeminal neurons onto second order sensory neurons. Effects specifically on TG neurons that project to cerebral dura were assessed by labeling dural nociceptors with DiI. Results Immunohistochemistry demonstrated that TRPV1 channels are present in cerebral dura, trigeminal ganglion, and in the trigeminal nucleus caudalis. Capsaicin, a TRPV1 agonist, produced depolarization and repetitive action potential firing in current clamp recordings and large inward currents in voltage clamp recordings from acutely dissociated TG neurons, demonstrating that TRPV1 channels are functional in trigeminal neurons. Capsaicin increased spontaneous excitatory postsynaptic currents (sEPSCs) in neurons of layer II in TNC slices, showing that these channels have a physiological effect on central synaptic transmission. Sumatriptan (10 μM), a selective anti-migraine drug inhibited TRPV1-mediated inward currents in TG. and capsaicin-elicited sEPSCs in TNC slices. The same effects of capsaicin and sumatriptan were found in acutely dissociated DiI-labeled TG neurons innervating cerebral dura. Conclusion Our results build on previous work indicating that TRPV1 channels in trigeminal nociceptors play a role in craniofacial pain. Our findings that TRPV1 is inhibited by the specific antimigraine drug sumatriptan, and that TRPV1 channels are functional in neurons projecting to cerebral dura suggests a specific role for these channels in migraine or cluster headache.

The Role of TRP Channels in Migraine

“…This high level of co-localization is consistent with reports that TRPV1 receptor activation in the dura stimulates CGRP release and subsequent vasodilatation [44][45][46]. Most studies report the presence of TRPV1 in presynaptic terminals of TNC [43,47], but see [48]. TRPV1 has also been detected in arteriole smooth muscle in the dura [43], albeit at low abundance [49].…”

“…TRPV1 is widely expressed in the anatomical substrates of migraine, particularly in soma of the trigeminal ganglion, nerve fibers, in central terminals in the TNC and in peripheral terminals within the dura [29,30,42,43]. Although previous studies had demonstrated the occurrence of TRPV1 receptors in the dura, the origin of the TRPV1 protein was not known.…”

“…Most studies report the presence of TRPV1 in presynaptic terminals of TNC [43,47], but see [48]. TRPV1 has also been detected in arteriole smooth muscle in the dura [43], albeit at low abundance [49]. TRPV1 is also reported in the cochlear arterioles where it has been hypothesized to mediate inner ear disturbances in migraine [50,51].…”

“…TRPV1 is present in peripheral and central nerve terminals [43,47] of trigeminal ganglion neurons where it mediates neurotransmitter release. Capsaicin stimulates release of CGRP from dural tissue [70] and TRPV1 activation of peripheral nerve terminals in the dura induces CGRP-dependent vasodilatation [44][45][46] which can be blocked by capsezepine, a TRPV1 antagonist [71].…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Capsaicin evokes CGRP release from dural tissue via TRPV1 activation, which in turn leads to CGRP-dependent vasodilatation (Eltorp et al, 2000). Furthermore, in trigeminal nucleus caudalis slices, capsaicin produces repetitive action potential formation and subsequent CGRP release that is inhibited by the antimigraine drug sumatriptan (Evans et al, 2012). Importantly, in the cat, application of the inflammatory soup to the dura increased blood flow and led to neuronal sensitization to mechanical stimuli; these responses were reversed by the TRPV1 antagonist SB705498 (Lambert et al, 2009).…”