High‐dose phenylephrine increases meningeal blood flow through TRPV1 receptor activation and release of calcitonin gene‐related peptide

Abstract

Background The α1‐adrenoceptor agonist, phenylephrine, is used at high concentrations as a mydriatic agent and for the treatment of nasal congestion. Among its adverse side‐effects transient burning sensations are reported indicating activation of the trigeminal nociceptive system. Methods Neuropeptide release, calcium imaging and meningeal blood flow recordings were applied in rodent models of meningeal nociception to clarify possible receptor mechanisms underlying these pain phenomena. Results Phenylephrine above 10 mM dose‐dependently released calcitonin gene‐related peptide (CGRP) from the dura mater and isolated trigeminal ganglia, whereas hyperosmotic mannitol at 90 mM was ineffective. The phenylephrine‐evoked release was blocked by the transient receptor potential vanilloid 1 (TRPV1) antagonist BCTC and did not occur in trigeminal ganglia of TRPV1‐deficient mice. Phenylephrine at 30 mM caused calcium transients in cultured trigeminal ganglion neurons responding to the TRPV1 agonist capsaicin and in HEK293T cells expressing human TRPV1. Local application of phenylephrine at micromolar concentrations to the exposed rat dura mater reduced meningeal blood flow, whereas concentrations above 10 mM caused increased meningeal blood flow. The flow increase was abolished by pre‐application of the CGRP receptor antagonist CGRP8‐37 or the TRPV1 antagonist BCTC. Conclusions Phenylephrine at high millimolar concentrations activates TRPV1 receptor channels of perivascular afferents and, upon calcium inflow, releases CGRP, which increases meningeal blood flow. Activation of TRPV1 receptors may underlie trigeminal nociception leading to cranial pain such as local burning sensations or headaches caused by administration of high doses of phenylephrine. Significance Phenylephrine is used at high concentrations as a mydriaticum and for treating nasal congestion. As adverse side‐effects burning sensations and headaches have been described. Phenylephrine at high concentrations causes calcium transients in trigeminal afferents, CGRP release and increased meningeal blood flow upon activation of TRPV1 receptor channels, which is likely underlying the reported pain phenomena.

Vascular actions of peripheral CGRP in migraine-like photophobia in mice

“…Alternatively, Dux et al. have recently reported that phenylephrine causes trigeminal nociception and increases meningeal blood flow through TRPV1 receptor activation and release of CGRP (83). Likewise, endothelin-1 on its own can induce pain-like behaviors in rodents (84) and can sensitize nociceptors and enhance release of glutamate in sensory neurons (85).…”

TRP Channels in the Focus of Trigeminal Nociceptor Sensitization Contributing to Primary Headaches

“…Results obtained in trigeminal neurons of TRPV1-deficient animals supported this observation. Phenylephrine-induced calcium transients and CGRP release were abolished in trigeminal ganglion neurons of TRPV1-deficient animals [36].…”

“…Trigeminal ganglia in situ or cultivated trigeminal ganglion cells from rodents are frequently used to measure the release of substances following stimulation with noxious agents that target TRPV1 and TRPA1 receptors [35,36]. Particularly quantification of CGRP release from trigeminal ganglia or trigeminal cell cultures induced by capsaicin is regarded as a parameter for trigeminal activation and sensitization [37,38].…”

“…Finally, trigeminal ganglion cell cultures have frequently been used to study the molecular properties of neurons and responses to endogenous and environmental mediators using calcium imaging [36,37]. Agonists and antagonists specifically targeting TRP receptor channels are employed to find out the role of TRPs in the neuronal activation [40].…”

“…Drugs used for other purposes than headache therapy may alter the sensitivity of nociceptors leading to uncomfortable or painful sensations upon administration. The α1-adrenoceptor agonist phenylephrine used at high concentrations as a mydriatic agent and for the treatment of nasal congestion may induce local burning sensation or headache as adverse side effect [36]. Recent experiments revealed that high concentrations of phenylephrine activate trigeminal neurons in rodent models of trigeminal nociception.…”