Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

Abstract

Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In DOR loxP controls SNC80 blocked the development of acute and chronic cephalic allodynia in the chronic nitroglycerin model, an effect that was lost in Dlx-DOR mice. In addition, the anti-allodynic effects of SNC80 were lost in a model of opioid induced hyperalgesia/medication overuse headache in Dlx-DOR conditional knockouts. In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.

Delta Opioid Receptor in Astrocytes Contributes to Neuropathic Cold Pain and Analgesic Tolerance in Female Mice

“…The first results on astrocytic DOR involvement in neuropathic pain and opioid analgesic tolerance reported here open the way to the exploration of the involvement of this DOR population in other pain paradigms including migraine (Dripps et al, 2020 ). Also, the role of astrocytic DOR in descending pain circuits may be explored (Price and Ray, 2019 ), as well as its impact on affective pain and on the anxio-depressive consequences of neuropathic pain (Birdsong et al, 2019 ; Cahill et al, 2020 ; Wahis et al, 2021 ).…”

“…Together with the previous demonstration that DOR-mediated analgesia was independent of microglial activation in a rat neuropathic pain model (Mika et al, 2014 ), this indicates that DOR on glial cells is not mainly involved in analgesia. Other DOR populations were shown to play a major role in DOR analgesia, in Nav1.8 peripheral neurons in inflammatory and neuropathic pain (Gaveriaux-Ruff et al, 2011 ; Nozaki et al, 2012 ) and in forebrain GABAergic neurons in migraine (Dripps et al, 2020 ). Therefore, the implication of astrocytic-DOR in the analgesic effect of novel DOR agonists including biased agonists may allow to better characterize these novel molecules (Conibear et al, 2020 ).…”

“…DOR in peripheral Nav1.8-positive nociceptive neurons and in immune cells were reported to protect against neuropathic pain (Gaveriaux-Ruff et al, 2011 ; Nozaki et al, 2012 ; Celik et al, 2016 ; Machelska and Celik, 2020 ). Also, DOR on forebrain GABAergic neurons were protective from migraine in the nitroglycerin model (Dripps et al, 2020 ). Peripheral DOR activation was more effective on neuropathic mechanical allodynia than heat hypersensitivity (Gaveriaux-Ruff et al, 2011 ; Labuz et al, 2016 ).…”

Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

“…The procedure for the cortical spreading depression (CSD) model is based on previously published work ( Chen and Ayata, 2017 ) that is commonly used to screen potential migraine preventives and further used in our own work ( Pradhan et al, 2014b ; Dripps et al, 2020 ; Bertels et al, 2021 ). Mice were grouped into sham and CSD groups and then further subdivide into ACY-738 (50 mg/kg, IP) or vehicle (i.e.…”

Alternative Splicing Mechanisms Underlying Opioid-Induced Hyperalgesia

“…Rodent models of OIH have advanced the understanding of the central nervous system (CNS) regions and molecular mechanisms underlying OIH [6][7][8][9][10][11]. Rodents repeatedly administered morphine presented hypersensitivity to noxious stimuli evidenced by the higher mechanical or thermal sensitivity to von Frey filaments and hot plate tests [7,9], and alterations of molecular pathways [6,[10][11][12].…”