Activation of central and peripheral transient receptor potential melastatin 8 increases susceptibility to spreading depolarization and facilitates trigeminal neuroinflammation

Mar 15, 2025The journal of headache and pain

Activation of cold-sensing channels in the brain and body may increase brain wave disturbances and promote nerve inflammation linked to headache

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Abstract

Activation of TRPM8 increased susceptibility to in the cortex.

TRPM8 is found throughout the cerebral cortex, mainly in cortical neurons.
Cortical TRPM8 activation raised the frequency of KCl-evoked spreading depolarization and worsened associated inflammation.
Inhibition of TRPM8 in the cortex showed minimal impact on these processes.
In primary trigeminal ganglion cell cultures, TRPM8 activation led to higher levels of (CGRP) and increased cyclooxygenase-2 expression.
The effects of TRPM8 activation on CGRP and neuroinflammation occurred through a mechanism dependent on calmodulin kinase II.

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BACKGROUND: Transient receptor potential melastatin 8 (TRPM8), a gene encoding a nonselective cation channel responsive to cold stimuli, has been implicated in migraine susceptibility. Despite this association, the role of TRPM8 to migraine pathogenesis remains elusive. This study aims to elucidate the potential role of TRPM8 in migraine pathophysiology.

METHODS: TRPM8 expression in the cortex and primary trigeminal ganglion (TG) cells was analyzed via immunostaining. The central role of TRPM8 was assessed using a (SD) model, where intracerebroventricular injections or topical applications of TRPM8 agonists and antagonists were administered to rats to investigate their effects on KCl-evoked SD and SD-induced cortical inflammation. The peripheral role of TRPM8 in migraine was evaluated using primary cultures of rat TG cells by analyzing the effects of TRPM8 activation on (CGRP) expression, release, and trigeminal neuroinflammation.

RESULTS: TRPM8 was homogeneously distributed in the cerebral cortex, predominantly co-localizing with cortical neurons. Activation of cortical TRPM8 increased the frequency of KCl-evoked SD and exacerbated SD-induced cortical inflammation. Interestingly. Interestingly, inhibition of cerebral TRPM8 had negligible effects. In TG primary cultures, TRPM8 activation upregulated CGRP expression and release and induced cyclooxygenase-2 (Cox2) upregulation via a calmodulin kinase II (CaMKII)-dependent mechanism.

CONCLUSIONS: TRPM8 activation increased susceptibility to SD and facilitated the effects of CGRP and trigeminal neuroinflammation, implicating that TRPM8 may contribute to migraine pathophysiology through central and peripheral mechanisms.

Key numbers

66.2–84.5%

Neurons Expressing TRPM8

Percentage of neurons in the cerebral cortex expressing TRPM8.

59.2±5.4%

Release Increase

Percentage of cells showing increased intracellular calcium levels after icilin treatment.

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Activation of central and peripheral transient receptor potential melastatin 8 increases susceptibility to spreading depolarization and facilitates trigeminal neuroinflammation

Abstract

Key numbers

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