A novel method for modeling facial allodynia associated with migraine in awake and freely moving rats

Abstract

Migraine is a neurovascular disorder that induces debilitating headaches associated with multiple symptoms including facial allodynia, characterized by heightened responsivity to normally innocuous mechanical stimuli. It is now well accepted that immune activation and immune-derived inflammatory mediators enhance pain responsivity, including in the trigeminal system. Nociceptive ("pain" responsive) trigeminal nerves densely innervate the cranial meninges. We have recently proposed that the meninges may serve as a previously unidentified, key interface between the peripheral immune system and the CNS with potential implications for understanding underlying migraine mechanisms. Our focus here is the development of a model for facial allodynia associated with migraine. We developed a model wherein an indwelling catheter is placed between the skull and dura, allowing immunogenic stimuli to be administered over the dura in awake and freely moving rats. Since the catheter does not contact the brain itself, any proinflammatory cytokines induced following manipulation derive from resident or recruited meningeal immune cells. While surgery alone does not alter immune activation markers, TNF or IL6 mRNA and/or protein, it does decrease gene expression and increase protein expression of IL-1 at 4 days after surgery. Using this model we show the induction of facial allodynia in response to supradural administration of either the HIV glycoprotein gp120 or inflammatory soup (bradykinin, histamine, serotonin, and prostaglandin E2), and the induction of hindpaw allodynia in our model after inflammatory soup. This model allows time and dose dependent assessment of the relationship between changes in meningeal inflammation and corresponding exaggerated pain behaviors.

Increased Asics Expression via the Camkii-CREB Pathway in a Novel Mouse Model of Trigeminal Pain

“…The model in this study is consistent with the definition, as mice received intermittent dural stimulation with acid for 16 days. Many scholars have shown that IS administration can produce a rat migraine model [3, 4, 7]. Compared with IS stimulation, administration of an acidic solution alone can also induce robust trigeminal pain and transcriptional expression of c-FOS and the neurotransmitter CGRP.…”

“…Second, we minimized the effects of surgery and anaesthesia by letting the mice recover from surgery for 5 days before the administration of the acid solution. Third, the acidic solution is more stable than IS, which contains small, easily degradable peptides [3, 4]. Fourth, we used dural, episodic stimulations in awake, freely moving mice to eliminate the effect of anaesthesia or surgery on the behavioural observations.…”

“…Dural administration of inflammatory soup (IS) is a well-established preclinical model of migraine in rats [3, 4]. However, the composition of IS is complex, as it contains unstable, small peptides that are difficult to store.…”

Nitroglycerin challenge induces lateralized headache in nasociliarynerve-ligated rats: implications for chronic migraine

“…The threshold for touch, cold, heat, and mechanical stimuli has been reported to be significantly reduced during an attack in 79% of migraineurs. Cutaneous allodynia spreads to the contralateral side of the head and body indicating central sensitization in 67% of the patients (2,4,5,15). Migraine patients with allodynia are more susceptible to triggering factors compared to nonallodynic patients.…”

PTEN inhibition preserves trigeminal nucleus caudalis neuron activation through tyrosine phosphorylation of the NR2B subunit at Tyr1472 of the NMDA receptor in a rat model of recurrent migraine

“…8 Stoelting Co, Chicago, IL, USA) and fitted with a cranial chamber under deep anesthesia with 10% chloral hydrate (i.p., 0.4 g/kg body weight). In this procedure, a 1-mm-wide craniotomy was performed above the superior sagittal sinus (SSS), and a stainless-steel cannula with removable cap was fixed to the bone around the opening in the skull using dental acrylic.…”