Calcitonin Gene-Related Peptide Receptor Antagonists: Beyond Migraine Pain—A Possible Analgesic Strategy for Osteoarthritis?

Bullock, Craig; Kelly, Sara

doi:10.1007/s11916-013-0375-2

Cited by 16 publications

(14 citation statements)

References 98 publications

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“…MIA treatment has previously been shown to increase the number of medium and large knee afferents that express CGRP (9). Together with our data, these findings suggest that MIA increases CLR and CGRP expression in an overlapping population of knee afferents, an intriguing finding given the proposed autoreceptor role of the CGRP receptor (23,28).…”

Section: Discussionsupporting

confidence: 85%

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Peripheral Calcitonin Gene‐Related Peptide Receptor Activation and Mechanical Sensitization of the Joint in Rat Models of Osteoarthritis Pain

Bullock

Wookey

Bennett

et al. 2014

Arthritis & Rheumatology

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ObjectiveTo investigate the role of the sensory neuropeptide calcitonin gene-related peptide (CGRP) in peripheral sensitization in experimental models of osteoarthritis (OA) pain.MethodsExperimental knee OA was induced in rats by intraarticular injection of monosodium iodoacetate (MIA) or by transection of the medial meniscus (MMT). Single-unit recordings of joint-innervating nociceptors were obtained in MIA- and saline-treated rats following administration of CGRP or the CGRP receptor antagonist CGRP 8–37. Effects of CGRP 8–37 were also examined in rats that underwent MMT and sham operations. Protein and messenger RNA (mRNA) levels of CGRP receptor components in the L3–L4 dorsal root ganglion (DRG) were investigated following MIA treatment.ResultsIn both the MIA and MMT groups, the mechanical sensitivity of joint nociceptors was enhanced compared to that in the control groups. Exogenous CGRP increased mechanical sensitivity in a greater proportion of joint nociceptors in the MIA-treated rats than in the saline-treated rats. Local blockade of endogenous CGRP by CGRP 8–37 reversed both the MIA- and MMT-induced enhancement of joint nociceptor responses. Joint afferent cell bodies coexpressed the receptor for CGRP, called the calcitonin-like receptor (CLR), and the intracellular accessory CGRP receptor component protein. MIA treatment increased the levels of mRNA for CLR in the L3–L4 DRG and the levels of CLR protein in medium and large joint afferent neurons.ConclusionOur findings provide new and compelling evidence implicating a role of CGRP in peripheral sensitization in experimental OA. Our novel finding of CGRP-mediated control of joint nociceptor mechanosensitivity suggests that the CGRP receptor system may be an important target for the modulation of pain during OA. CGRP receptor antagonists recently developed for migraine pain should be investigated for their efficacy against pain in OA.

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Section: Discussionsupporting

confidence: 85%

“…CGRP is implicated in the generation of migraine pain (28) and inflammatory joint pain (11), and there are now strong clinical and preclinical associations between the levels of CGRP in joints and pain during OA. Whether a direct relationship or integrated, causal mechanism exists is unknown.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Calcitonin Gene‐Related Peptide Receptor Activation and Mechanical Sensitization of the Joint in Rat Models of Osteoarthritis Pain

Bullock

Wookey

Bennett

et al. 2014

Arthritis & Rheumatology

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“…Interestingly, this antibody was also effective in relieving pain-related behavior in rat models of osteoarthritis (79). This activity is consistent with preclinical observations with olcegepant and the predicted role of CGRP in joint pain (80). …”

Section: Cgrp As a Therapeutic Target For Migrainesupporting

confidence: 90%

Calcitonin Gene-Related Peptide (CGRP): A New Target for Migraine

Russo

2015

Annu. Rev. Pharmacol. Toxicol.

309

305

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Migraine is a neurological disorder that manifests as a debilitating headache associated with altered sensory perception. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. Clinical trials carried out during the past decade have proved that CGRP receptor antagonists are effective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation. Despite this progress in the clinical arena, the mechanisms by which CGRP triggers migraine remain uncertain. This review discusses mechanisms whereby CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Future studies on epistatic and epigenetic regulators of CGRP actions are expected to shed further light on CGRP actions in migraine. In conclusion, targeting CGRP represents an approachable therapeutic strategy for migraine.

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“…Second, the increase in SP may function to regulate peripheral levels of CGRP [123]. The latter is particularly intriguing, given that CGRP has been shown to propagate inflammation in high quantities but provides potent [123][124][125] anti-inflammatory actions in low concentrations via TTX channel inhibition.…”

Section: Calcitonin Gene Regulated Peptide and Substance-pmentioning

confidence: 99%

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

Butts¹,

Dunning²

2016

Int J Phys Med Rehabil

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There are a number of biochemical, biomechanical, endocrinological and neurovascular mechanisms underpinning the anti-nociceptive and anti-inflammatory effects of dry needling (DN). While myofascial trigger points likely play a role in peripheral pain, a diagnostic tool for localizing them has not been validated, and DN studies that have targeted trigger points to elicit localized twitch responses have reported mixed results. Therefore, the mechanism responsible for DN-mediated analgesia may be more complicated. DN activates opioid-based pain reduction, mediated by endogenous cannabinoids and the sympathetic nervous system, and non-opioid pain relief via serotonin and norepinephrine from the brain stem. DN also triggers the hypothalamic-pituitary-adrenal axis centrally and the corticotropin releasing hormone-proopiomelanocortin-corticosteroid axis locally to inhibit cox-2, reducing inflammatory cytokines. Recent studies demonstrate that DN combined with mechanical and/or electrical stimulation may reverse PKC-mediated peripheral hyperalgesic priming by normalizing nociceptive channels, to include TRPV, ASIC, TTX and P2X/Y. Electrical DN (EDN) stimulates immune cells, fibroblasts and keratinocytes to release CGRP and substance-P, altering the stimulation of TTX receptors to reverse hyperalgesia. It also encourages the supraoptic nucleus to release oxytocin to quiet ASIC receptors peripherally and stimulate opioid interneurons spinally. Moreover, EDN inhibits ERK1/2 kinase pathways of inflammation in the spinal cord and stimulates Aδ fibers and N/OFQ to reverse C-fiber mediated central changes. Mechanotransduction of fibroblasts and peripheral nerves via TRPV1 and P2X/Y-mediated intracellular Ca 2+ wave propagation and subsequent activation of the nucleus accumbens inhibits spinal pain transmission via glycinergic and opioidergic interneurons. The increased ATP is metabolized to adenosine, which activates P1 purinergic receptors, events considered key to DN analgesia and rho kinase-based tissue remodeling. Mechanotransduction-mediated release of histamine further explains analgesia secondary to needling points distal to pain. DN-mediated analgesia is dependent on a number of synergistic physiologic events involving biochemical and mechanical processes in neural, connective and muscle tissue.

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Calcitonin Gene-Related Peptide Receptor Antagonists: Beyond Migraine Pain—A Possible Analgesic Strategy for Osteoarthritis?

Cited by 16 publications

References 98 publications

Peripheral Calcitonin Gene‐Related Peptide Receptor Activation and Mechanical Sensitization of the Joint in Rat Models of Osteoarthritis Pain

Peripheral Calcitonin Gene‐Related Peptide Receptor Activation and Mechanical Sensitization of the Joint in Rat Models of Osteoarthritis Pain

Calcitonin Gene-Related Peptide (CGRP): A New Target for Migraine

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

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