Peripherally Acting Opioids in Orofacial Pain

Liu, Qing; He, Hongwen; Mai, Lijia; Yang, Shengyan; Fan, Wenguo; Huang, Fang

doi:10.3389/fnins.2021.665445

Cited by 3 publications

(6 citation statements)

References 157 publications

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“…Dura mater, the source of nociceptive input that is likely required for headache, contains afferents from trigeminal ganglion neurons, blood vessels, fibroblasts, and various immune cells 57,58 . Immune cells, including macrophages, granulocytes, and lymphocytes, are important sources of endogenous opioids 17,59,60 . M2 macrophages have been shown to contain and release Met‐enkephalin, and transferred polarized macrophages could reduce chronic constriction injury‐induced mechanical hypersensitivity by releasing opioid peptides 61 .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of dual enkephalinase inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors

et al. 2023

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Objective The aim of this study was to evaluate whether elevating levels of enkephalin by inhibiting their degradation can attenuate stress‐induced migraine‐like behaviors in mice. Background Previous studies in animals have suggested the delta opioid receptor (DOR) as a novel migraine target. The primary endogenous ligands for DOR are enkephalins and their levels can be increased by pharmacological inhibition of enkephalinases; however, it is not clear whether enkephalinase inhibition can be efficacious in preclinical migraine models through activation of DOR or whether other opioid receptors might be involved. Further, it is not clear whether opioid receptors in the central nervous system are necessary for these effects. Methods This study used a model of repetitive restraint stress in mice that induces periorbital hypersensitivity and priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg). Von Frey filaments were used to measure periorbital mechanical thresholds and grimace scores were evaluated by observing mouse facial features. Animals were treated with the dual enkephalinase inhibitor (DENKI) PL37. Results On day two post‐stress, PL37 given to mice via either intravenous injection (10 mg/kg) or oral gavage (20 mg/kg) significantly attenuated stress‐induced periorbital hypersensitivity and facial grimace responses. Additionally, both intravenous (10 mg/kg) and oral gavage (20 mg/kg) of PL37 prior to SNP (0.1 mg/kg) administration on day 14 post‐stress significantly reduced SNP‐induced facial hypersensitivity. Injection of the DOR antagonist naltrindole (0.1 mg/kg) but not the mu‐opioid receptor antagonist CTAP (1 mg/kg) prior to PL37 treatment blocked the effects. Finally, pretreatment of mice with the peripherally restricted opioid receptor antagonist naloxone methiodide (5 mg/kg) blocked the effects of PL37. Conclusions These data demonstrate that inhibiting enkephalinases, and thus protecting enkephalins from degradation, attenuates stress‐induced migraine‐like behavior via activation of peripheral DOR. Peripheral targeting of endogenous opioid signaling may be an effective therapeutic strategy for migraine.

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Section: Discussionmentioning

confidence: 99%

Efficacy of dual enkephalinase inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors

et al. 2023

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“…38 Opioid receptors are mainly divided into three subtypes: μ-, δ-and κ-opioid receptors (MOR, DOR and KOR, respectively), which are also widely distributed in the trigeminal system. 38…”

Section: Opioid Peptide Opmentioning

confidence: 99%

“…However, conventional medicines have inferior efficacy in relieving orofacial pain and often accompanied by various adverse reactions, such as respiratory depression, constipation, cardiotoxicity and dizziness. 38 Besides, lots of orofacial pain still lack effective and specific therapeutic drugs at present. Given the role of neuropeptides such as CGRP, SP, GAL and OP in orofacial pain or inflammation, many scholars have begun to explore the potential applications of their analogues, agonists or antagonists in the treatment of various orofacial pain.…”

Section: Neuropep Tide S and Their Ag Onis Ts Or Antag Onis Ts For Pa...mentioning

confidence: 99%

“…Opioids, which exert antinociceptive and anti-inflammatory effects in orofacial pain by acting on opioid receptors, [40][41][42] are one of the main drugs for treating orofacial pain, and are the most effective drugs for treating moderate-to-severe pain. 38 Similarly, CGRP antagonist, CGRP receptor antagonist and CGRP monoclonal antibodies (CGRP-mAbs) have been widely used in the treatment of orofacial migraine and it has been proven that erenumab, fremanezumab, galcanezumab, and others are effective drugs for treating migraine. 69,70 Even, TA B L E 1 Neuropeptides and their agonists or antagonists in orofacial pain.…”

Section: Neuropep Tide S and Their Ag Onis Ts Or Antag Onis Ts For Pa...mentioning

confidence: 99%

“…Classical EOPs are divided into endorphins, enkephalins and dynorphins. OPs are expressed in the central and peripheral nervous system, neuroendocrine tissues, immune cells and glial cells 38 . Opioid receptors are mainly divided into three subtypes: μ‐, δ‐ and κ‐ opioid receptors (MOR, DOR and KOR, respectively), which are also widely distributed in the trigeminal system 38 …”

Section: Orofacial Pain‐related Neuropeptidesmentioning

confidence: 99%

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Role of neuropeptides in orofacial pain: A literature review

Wang,

Liu,

Gou

et al. 2024

J of Oral Rehabilitation

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BackgroundNeuropeptides play a critical role in regulating pain and inflammation. Despite accumulating evidence has further uncovered the novel functions and mechanisms of different neuropeptides in orofacial pain sensation and transmission, there is deficient systematic description of neuropeptides' pain modulation in the orofacial region, especially in the trigeminal system.ObjectivesThe present review aims to summarise several key neuropeptides and gain a better understanding of their major regulatory roles in orofacial inflammation and pain.MethodsWe review and summarise current studies related to calcitonin gene‐related peptide (CGRP), substance P (SP), opioid peptide (OP), galanin (GAL) and other neuropeptides' functions and mechanisms as well as promising targets for orofacial pain control.ResultsA number of neuropeptides are clearly expressed in the trigeminal sensory system and have critical functions in the transduction and pathogenesis of orofacial pain. The functions, possible cellular and molecular mechanisms have been introduced and discussed. Neuropeptides and their agonists or antagonists which are widely studied to be potential treatment options of orofacial pain has been evaluated.ConclusionsVarious neuropeptides play important but distinct (pro‐nociceptive or analgesic) roles in orofacial pain with different mechanisms. In summary, CGRP, SP, NPY, NKA, HK‐1, VIP mainly play proinflammatory and pro‐nociceptive effects while OP, GAL, OXT, OrxA mainly have inhibitory effects on orofacial pain.

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