Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents

Abstract

Despite the relatively high prevalence of migraine or headache, the pathophysiological mechanisms triggering headache-associated peripheral hypersensitivities, are unknown. Since nitric oxide (NO) is well known as a causative factor in the pathogenesis of migraine or migraine-associated hypersensitivities, a mouse model has been established using systemic administration of the NO donor, nitroglycerin (NTG). Here we tried to investigate the time course development of facial or hindpaw hypersensitivity after repetitive NTG injection. NTG (10 mg/kg) was administrated to mice every other day for nine days. Two hours post-injection, NTG produced acute mechanical and heat hypersensitivity in the hind paws. By contrast, cold allodynia, but not mechanical hypersensitivity, occurred in the facial region. Moreover, this hindpaws mechanical hypersensitivity and the facial cold allodynia was progressive and long-lasting. We subsequently examined whether the depletion of capsaicin-sensitive primary afferents (CSPAs) with resiniferatoxin (RTX, 0.02 mg/kg) altered these peripheral hypersensitivities in NTG-treated mice. RTX pretreatment did not affect the NTG-induced mechanical allodynia in the hind paws nor the cold allodynia in the facial region, but it did inhibit the development of hind paw heat hyperalgesia. Similarly, NTG injection produced significant hindpaw mechanical allodynia or facial cold allodynia, but not heat hyperalgesia in transient receptor potential type V1 (TRPV1) knockout mice. These findings demonstrate that different peripheral hypersensitivities develop in the face versus hindpaw regions in a mouse model of repetitive NTG-induced migraine, and that these hindpaw mechanical hypersensitivity and facial cold allodynia are not mediated by the activation of CSPAs.Key words allodynia; nitroglycerin; migraine; resiniferatoxin; transient receptor potential type V1 (TRPV1) Migraine, a multifactorial primary headache disorder, is characterized by one-sided, severe, and pulsatile headaches. 1) During the headache phase, stimuli that are generally innocuous, such as ambient light or sound, can be unpleasant during headache. Most patients with migraines experience increased cutaneous sensitivity to non-noxious mechanical, cold, and thermal stimulation of the skin of the cephalic or non-cephalic regions of the body. 2) While central sensitization could contribute to the mechanisms underlying this cutaneous hypersensitivity, 2,3) the exact mechanisms are poorly understood.Nitroglycerin (NTG), a nitric oxide (NO) donor and effective vasodilator, is generally used to treat patients with angina. One of the main side effects of NTG is migraine, which may develop within minutes, or up to four hours post-administration. 4) Systemic NTG activates nociceptive neurons in areas of the mouse brain. 5) In mice, a single injection of NTG induces acute mechanical, cold, and thermal hypersensitivity, which persists up to four hours post-injection. 3,6) Recently Pradhan et al. reported that repetitive injections of NTG induced chron...

Microglial NLRP3 inflammasome activation mediates IL-1β release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model

“…NTG-induced migraine is related to its metabolite NO; therefore, the sGC stimulator VL-102 can replace NTG in the model [36]. In addition, Sol-Ji Kim reported the opposite result, which may be related to selecting different facial area; he tested whisker pads rather than periorbital area [37]. In addition to headache, CM patients may experience hyperalgesia of extracephalic areas, which is an outward manifestation of central sensitization [4, 38].…”

Behavioral and cognitive animal models in headache research

“…In the study, NTG administration increased acetone sensitivity in the forehead only in nasociliary nerve ligated side [46]. In a NTG-induced mouse model of chronic migraine, the duration of withdrawal responses to acetone in the facial region were significantly increased in mice treated with NTG compared to control [52]. Alvarez et al showed an enhanced response to acetone in neuropathic mice in their model for posttraumatic trigeminal neuropathic pain [53].…”

Animal models of migraine and experimental techniques used to examine trigeminal sensory processing

“…For example, Brennan et al showed that a higher dose of nitroglycerin was required to elicit differences in thermal allodynic responses in transgenic mice compared to a lower dose required for mechanical sensation [85]. In addition, Kim et al showed differential mechanical and thermal sensitivities in the orofacial region and hind paw following chronic nitroglycerin [174]. In this study, cold was assessed on the face via acetone, while heat on the paw, likely due to the difficulty to direct a thermal stimulus to the orofacial region of an awake, freely moving animal.…”