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. 2012 May;52(5):773-84.
doi: 10.1111/j.1526-4610.2011.02053.x. Epub 2012 Jan 30.

Sumatriptan inhibits TRPV1 channels in trigeminal neurons

Miles Steven Evans  1 , Xiangying Cheng, Joseph A Jeffry, Kimberly E Disney, Louis S Premkumar
Affiliations

Sumatriptan inhibits TRPV1 channels in trigeminal neurons

Miles Steven Evans et al. Headache. 2012 May.

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, 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, in trigeminal ganglion, and in the TNC. 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 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 antimigraine drug, inhibited TRPV1-mediated inward currents in TG and capsaicin-elicited spontaneous excitatory postsynaptic currents 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.

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Conflict of interest statement

Conflicts of Interest:

No conflict for any author

Figures

Figure 1
Figure 1. TRPV1 immunohistochemistry in trigeminal ganglion and dura
(A to C) Trigeminal ganglion is labeled for TRPV1 and seen in fluorescent, differential interference contrast (DIC), and merged images. Large numbers of cell bodies express TRPV1. (D and E) Magnified sections show TRPV1 labeling is in a minority of neurons, primarily small neurons. (F) Cerebral dura has abundant TRPV1 signal especially near blood vessels.
Figure 2
Figure 2. TRPV1 immunohistochemistry in trigeminal nucleus
Coronal slices of spinal trigeminal nucleus are shown at the level of the oral (top), interpolar (middle) and caudal (bottom) subnuclei. At each level, immunoreactivity for TRPV1 (left), NeuN (middle) and merged images are shown. The caudal subnucleus has TRPV1-containing fibers in the superficial layers (arrows), but there is no TRPV1 immunoreactivity in the oral and interpolar subnuclei. TRPV1 immunopositive cell bodies are absent in all parts of the spinal trigeminal nucleus.
Figure 3
Figure 3. TRPV1 depolarization and inward currents in trigeminal ganglion neurons
(A) The TRPV1 agonist capsaicin (Cap, 100 nM) produced a strong depolarization and action potential firing. (B) Capsaicin produced concentration-dependent inward currents.
Figure 4
Figure 4. TRPV1 modulates spontaneous EPSCs in neurons of the trigeminal nucleus caudalis (TNC)
(A) Capsaicin reversibly increased the frequency of sEPSCs. Top figures show the increase on a slow time scale, and lower figures on a faster time scale. (B) The increase in sEPSCs is associated with a marked increase in frequency of sEPSCs but (C) not in amplitude. If synaptic potentials were blocked, capsaicin had no effect on neurons of the TNC (data not shown).
Figure 5
Figure 5. Sumatriptan inhibits TRPV1 currents in TG neurons
(A) Sumatriptan (10 μM) inhibited inward currents evoked by capsaicin (100 nM) in a TG neuron. (B) The mean inhibition of capsaicin currents was 70% (N = 13 TG neurons). Error bars indicate SD. Sumatriptan inhibition of capsaicin currents was statistically significant by ANOVA (P = 0.016 by ANOVA). * indicates paired t test P = 0.0009, ** indicates P = 0.0003. (C) TG neurons innervating cerebral dura were labeled with DiI (D) Capsaicin currents in labeled dural TG neurons showed robust inhibition by sumatriptan.
Figure 6
Figure 6. Sumatriptan inhibits TRPV1-mediated sEPSCs in TNC
(A) In most neurons, repeated application of capsaicin caused a decrease in sEPSC response, as shown. (B) In this neuron, the frequency of sEPSCs is significantly reduced with the second application of capsaicin. (C) A histogram summarizing average results for repeated capsaicin application. (D) To control for activity-dependent decreases in capsaicin responses, capsaicin was applied first with sumatriptan, then again without sumatriptan, since without sumatriptan the first response is expected to be larger. In the example shown, sumatriptan inhibited the first capsaicin response, and the second response is larger. (E) sEPSC frequency was decreased by sumatriptan, but (F) the amplitude of sEPSCs was not affected by sumatriptan. (G) Histogram summarizing sumatriptan inhibition of capsaicin-mediated sEPSCs. Error bars indicate SD, * indicates P = 0.049 t test.
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