Molecular basis for adenosine A3 receptor agonists in the treatment of migraine

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Project Summary/Abstract Despite recent advances with new therapies, a huge proportion of migraine patients are still unable to use established therapeutics. For many patients, treatments are not effective, even newly approved CGRP mAbs have response rates of only ~50%. For others they are unsafe due to contraindications (triptans), or like opioids, not suited for long term use, even exacerbating existing migraine headache. This illustrates that there are still major gaps in our understanding of migraine mechanisms. It is therefore imperative that we investigate the underlying molecular mechanisms involved, geared towards identifying novel therapeutic targets with potential for rapid translation to the clinic. Recent data have identified the adenosine A3 receptor (A3AR) as a novel target for pain. Our recent work has also established that production of the highly noxious reactive nitroxidative species, peroxynitrite (PN), causes downstream modifications to glutamatergic signaling and NLRP3/IL-1β-driven neuroinflammation, to mediate nociceptive spinal sensitization. We show that A3AR agonists attenuate these nociceptive mechanisms in diverse rodent models of neuropathic pain, providing persistent pain relief. Despite this, little is known about A3AR-PN mechanisms in trigeminovascular migraine models. However, our preliminary data demonstrate that A3AR are expressed in important peripheral and central regions along the migraine pain pathway, and A3AR agonists inhibit migraine-like responses in several rodent models of migraine that are highly predictive of therapeutic efficacy. Additional data also implicate both PN and NLRP3 production in mediating migraine-like nociceptive responses. This is exciting as A3AR agonists are already in clinical trials in non-pain disorders, have a good safety profile, and appear well suited for chronic pain management. Based on these observations we hypothesize that PN production and activation of its downstream nociceptive signaling cascade is involved in neuronal and behavioral outcomes in preclinical models of migraine-like headache, and A3AR agonists inhibit these outcomes, via modulation of this PN signaling cascade. Our goal in Aim 1 will be to validate A3AR as a novel therapeutic target for migraine-like headache using validated preclinical models of acute and chronic migraine-like headache and established behavioral and electrophysiological techniques. We will also measure the temporal expression and localization of A3AR along the migraine pain pathway. In Aim 2, using pharmacological and genetic approaches, with biochemical analyses, we will test whether the beneficial effects of A3AR agonists are exerted through inhibition of PN production, and attenuation of post-translational modifications to neuronal and glial proteins involved in nociceptive glutamatergic neurotransmission and NLRP3/IL-1β-driven neuroinflammation. Our results are anticipated to provide novel insights into the molecular neuropharmacology related to dural-trigeminovascular activation in migraine. Importantly, these studies will validate A3AR as a novel target for migraine treatment, which should accelerate ‘proof-of-concept’ clinical studies, leading to a new translational effort in the treatment of migraine-like headache disorders.