Amylin Analog Pramlintide Induces Migraine‐like Attacks in Patients

Abstract

Objective Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene‐related peptide (CGRP). Methods Thirty‐six migraine without aura patients were enrolled in a randomized, double‐blind, 2‐way, crossover, positive‐controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on 2 different experimental days. Furthermore, translational studies in cells and mouse models, and rat, mouse and human tissue samples were conducted. Results Thirty patients (88%) developed headache after pramlintide infusion, compared to 33 (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine‐like attacks after pramlintide infusion, compared to 19 patients (56%) after CGRP (p = 0.180). The pramlintide‐induced migraine‐like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide‐provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice. Interpretation Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. ANN NEUROL 2021;89:1157–1171

Female mice exhibit a more sensitive automated squint response to pain induced by CGRP and amylin

“…In addition, amylin was effective at inducing squint in only female mice, even at the relatively high single dose that was tested. A similar observation of greater responses in female mice to the same dose of amylin has been reported with light aversion and cutaneous sensitivity tests [5]. While the reason for the greater sensitivity to IP CGRP and amylin in female mice is not known, it is interesting that Dussor and colleagues reported that only female mice responded to direct application of CGRP onto the dura [1].…”

“…The ability of amylin to induce squint in mice builds on the recent report that the amylin analog pramlintide induces migraine-like headache in patients and that amylin induced two migraine-like symptoms of light aversion and cutaneous hypersensitivity in mice [5]. While our experiments were not designed for direct comparison between CGRP and amylin, the relatively small amylin-induced squint response is consistent with the observations that pramlintide and amylin also appeared to be less potent than CGRP in inducing migraine-like headaches and symptoms in patients and mice, respectively [5]. Future studies are needed to ascertain whether the difference in efficacy might reflect differences in receptors i.e., CGRP binds the canonical CGRP receptor to a greater degree than amylin [8].…”

“…We then used the automated squint software to assess the photic blink response in mice, with validation of automated results using electromyography (EMG). Finally, the automated assay was used to test the sex-dependent effect of the CGRP-related peptide amylin, which binds one of the two CGRP receptors [8] and the amylin analog pramlintide and amylin have recently been shown to induce migraine in patients and migraine-like symptoms in mice, respectively [5].…”

Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

“…As with CGRP, levels of amylin are also elevated in obese individuals [79]. Amylin and its analogues are known to induce migraine attacks in patients with migraine [80]. As such, the dual increase of serum amylin and CGRP in obesity could contribute to the increased risk of migraine associated with obesity.…”

Response to letter to the Editor: Assessing migraine therapeutics

“…It has been suggested that the location of the AMY 1 receptor likely determines which hormone/neuropeptide (amylin or CGRP) may activate it (11). For example, it has been postulated that the AMY 1 receptor may be a candidate for CGRP/ amylin signaling in the trigeminal ganglia in migraine pathophysiology (10,11) whereas, when expressed in other tissues/organs, the AMY 1 receptor may mediate different biological functions of amylin (11).…”