Protein kinase Cδ as a neuronal mechanism for headache in a chronic intermittent nitroglycerin model of migraine in mice

Abstract

Migraine is one of the most common neurological disorders characterized by recurrent attacks of typically throbbing and unilateral headaches, affecting up to 20% of the population worldwide. Despite the high prevalence and severity of this primary headache disorder, it remains to be a challenge to fully understand and treat migraine headaches. By characterizing and validating a mouse migraine model, this study aimed to investigate the functional contribution of protein kinase C (PKC) isoforms in migraine. In this study, we identified the presence of migraine-like ongoing pain in mice after chronic intermittent treatment with nitroglycerin (NTG). The peptide antagonist of calcitonin gene-related peptide α-CGRP (8-37), but not topiramate nor sumatriptan, effectively blocked ongoing pain and elicited pain relief-induced conditioned place preference in NTG-treated mice. Prominent activation of PKCδ was observed in chronic NTG-treated mice. Functional inhibition of PKCδ significantly attenuated ongoing spontaneous pain in chronic NTG-treated mice. Furthermore, we recapitulated the NTG-triggered migraine behavior in wild-type mice, but not in PKCδ-null mice. In response to repeated administration of NTG, ongoing spontaneous pain was not developed in mice lacking the specific PKC isoform. This study identified the presence of ongoing pain in mice treated with NTG, a known human migraine trigger that closely resembles the common manifestation of spontaneous migraine attacks in humans. These findings demonstrated a critical regulatory role of PKCδ in migraine pathophysiology, which may offer new pharmacological targets for antimigraine treatment.

Atogepant – an orally-administered CGRP antagonist – attenuates activation of meningeal nociceptors by CSD

“…In agreement with all pivotal clinical studies on the efficacy of the CGRP monoclonal antibodies as well as the gepants (1)(2)(3)(4)(5)(6)(7), behavioral studies in rodents have found therapeutic effects of CGRP inhibitors in several models of headache, including systemic glyceryl trinitrate (GTN) (8)(9)(10)(11), dural application of inflammatory mediators (12) or potassium chloride (13,14), spontaneous facial hypersensitivity (10,15), traumatic brain injury (16,17), medication overuse headache (18), CGRP-induced photophobia (19), and umbelluloneinduced hyperalgesic priming (20), and electrophysiological or fos expression studies found inhibitory effects of these agents in response to GTN or other nitric oxide donors (21)(22)(23), or direct electrical or chemical stimulation of the dura (24,25), but not cortical spreading depression (CSD) (24) -where the observed reduction in percentage of activated Ad did not reach statistical significance during the relatively short (1 hr) post-CSD recording period.…”

Novel insight into atogepant mechanisms of action in migraine prevention

“…anti-CGRP-mAbs (monoclonal antibodies), anti-CGRP/R-mAbs, CGRP receptor antagonists] in migraine prevention 8-12 and resolution. 13 , 14 In agreement with these clinical studies, behavioural studies in rodents have found therapeutic effects of CGRP inhibitors in several models of headache, including systemic glyceryl trinitrate (GTN), 15-18 dural application of inflammatory mediators 19 or potassium chloride, 20 , 21 medication overuse headache, 22 CGRP-induced photophobia 23 and umbellulone-induced hyperalgesic priming. 24 Similarly, physiological studies found inhibitory effects of these agents in response to systemic administration of GTN or other nitric oxide donors, 25-27 direct electrical or chemical stimulation of the dura 28 , 29 and cortical spreading depression (CSD).…”

CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine

“…7 ), suggesting a potential causal relationship between these neurons and migraine chronification. Although prior studies have indicated that sensitization of TG neurons are responsible for the pain in this model [ 49 – 51 ], our study provides an alternative perspective that there is a cell-type specific central mechanism that regulates the trigeminal or extra-trigeminal nociceptive input in CM. Notably, specifically silencing these CeA PKC-δ positive neurons with chemogenetics, without directly intervening the TG, could still reduce the CGRP expression in the TG, which further suggests a possible top-down mechanism of these neurons in regulating pain.…”