CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache

Aim Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. Methods Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. Results In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. Interpretation Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

Sustained exposure to acute migraine medications combined with repeated noxious stimulation dysregulates descending pain modulatory circuits: Relevance to medication overuse headache

Background Loss of conditioned pain modulation/diffuse noxious inhibitory controls has been demonstrated in patients with migraine and medication overuse headache. We hypothesized that exposure to acute migraine medications may lead to dysregulation of central pain modulatory circuits that could be revealed by evaluating diffuse noxious inhibitory controls and that prior noxious stimulus is required for a loss of the diffuse noxious inhibitory control response in rats exposed to these medications. Methods Rats were “primed” by continuous infusion of morphine or one of two doses of sumatriptan. Diffuse noxious inhibitory control was evaluated at the end of drug-priming (day 7) and again after sensory thresholds returned to baseline (day 21). The Randall-Selitto hindpaw pressure test was used as the test stimulus and forepaw capsaicin injection served as the conditioning stimulus. Results Morphine-primed rats showed opioid-induced hyperalgesia accompanied by a loss of diffuse noxious inhibitory controls on day 7. Sumatriptan-primed rats did not develop hyperalgesia or loss of diffuse noxious inhibitory controls on day 7. Morphine-primed and high-dose sumatriptan-primed rats only had a loss of diffuse noxious inhibitory control on day 21 if they received a capsaicin injection on day 7. Conclusions Prolonged exposure to migraine treatments followed by an acute nociceptive stimulation caused long-lasting alterations in descending pain modulation, shown by a loss of diffuse noxious inhibitory controls. Morphine was more detrimental than sumatriptan, consistent with clinical observations of higher medication overuse headache risk with opioids. These data suggest a mechanism of medication overuse headache by which migraine medications combined with repeated episodes of pain may amplify the consequences of nociceptor activation and increase the probability of future migraine attacks as well as risk of medication overuse headache.

The milestone effect of DNIC in our understanding of pain

While thousands of articles are published each year on pain, only a few have such a major impact on the understanding of pain mechanisms as the landmark paper discussed in this chapter; published by Le Bars and colleagues in 1979, it introduced the concept of diffuse noxious inhibitory control (DNIC; also called diffuse noxious inhibition) mechanisms. Although this work is more than three decades old, it still has a major influence on both the understanding of pain mechanisms and the development of clinical approaches. It is known that apparently similar pain may be caused by different mechanisms: one may be caused by amplified excitatory mechanisms while the other may be related to a deficit of endogenous pain modulation, such as DNIC or conditioned pain modulation (or CPM); these will not respond to the same treatment. The work by Le Bars and colleagues provided a new understanding of mechanisms underlying pain.