Effect of neurokinin A, substance P and calcitonin gene related peptide in peripheral hyperalgesia in the rat paw

Nakamura-Craig, Meire; Gill, Balvinder Kaur

doi:10.1016/0304-3940(91)90819-f

Cited by 79 publications

(54 citation statements)

References 14 publications

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“…Consistent with the proposed mechanism of hyperalgesia priming, the effect that CGRP has on TTX channels is PKA and PKC dependent [126] and repeated or sustained exposure to CGRP could tip the balance toward PKC-ε and flip the cellular switch from an acute to a chronic pain response [127,128]. It is also interesting to note that while a series of high-dose injections of CGRP are required to stimulate PKC-ε, a sustained low-dose CGRP managed by SP and stimulated by EDN may be able to flip the switch in the opposite direction [124].…”

Section: Calcitonin Gene Regulated Peptide and Substance-pmentioning

confidence: 57%

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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Section: Calcitonin Gene Regulated Peptide and Substance-pmentioning

confidence: 57%

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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“…In fact, CGRP release is commonly used as an index of nociceptor activation. However, injection of CGRP into rodent and human skin has generally been without a direct hyperalgesic effect, although spinal administration sensitized nociceptive transmission and enhanced effects of other mediators, such as substance P (5,(18)(19)(20). The reason may be that the literature on CGRP as a modulator of heat nociception, at least in the mouse, has been complicated by the previously unknown strain-dependence of CGRP sensitivity and gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…The reason may be that the literature on CGRP as a modulator of heat nociception, at least in the mouse, has been complicated by the previously unknown strain-dependence of CGRP sensitivity and gene expression. That is, the failure of prior studies to demonstrate peripheral CGRP effects might be due to the use of CGRP-rich and, thus, CGRP-insensitive mouse or rat strains (18,19).…”

Section: Discussionmentioning

confidence: 99%

“…Both activation of PKA and calcium influx are sufficient to induce sensitization to heat of nociceptive neurons and to enhance their stimulated release of CGRP (13)(14)(15)(16). Nonetheless CGRP has not previously been shown to exert any acute sensitizing effects on cutaneous nociceptor endings or to induce heat hyperalgesia (17)(18)(19)(20). We report here that CGRP gene expression, content, release, and function are all highly strain-dependent, that this factor accounts for the inherited strain differences in thermal response, and that, in appropriately chosen strains, CGRP does induce heat hyperalgesia.…”

mentioning

confidence: 99%

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Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene

Mogil

Miermeister

Seifert

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

151

109

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Heat sensitivity shows considerable functional variability in humans and laboratory animals, and is fundamental to inflammatory and possibly neuropathic pain. In the mouse, at least, much of this variability is genetic because inbred strains differ robustly in their behavioral sensitivity to noxious heat. These strain differences are shown here to reflect differential responsiveness of primary afferent thermal nociceptors to heat stimuli. We further present convergent behavioral and electrophysiological evidence that the variable responses to noxious heat are due to strain-dependence of CGRP expression and sensitivity. Strain differences in behavioral response to noxious heat could be abolished by peripheral injection of CGRP, blockade of cutaneous and spinal CGRP receptors, or long-term inactivation of CGRP with a CGRP-binding Spiegelmer. Linkage mapping supports the contention that the genetic variant determining variable heat pain sensitivity across mouse strains affects the expression of the Calca gene that codes for CGRP␣.calcitonin gene-related peptide ͉ genetic ͉ Calca ͉ nociceptors ͉ pain H umans display wide individual variability in sensitivity to pain.Although the relative importance of genes versus experience in human pain perception is unclear, recent studies have shown that mouse strains display large differences in behavioral pain sensitivity that are heritable (1). These same studies revealed genetic correlations between baseline thermal nociception and the hypersensitivity states associated with inflammatory and neuropathic pain (2). Of the strains examined, AKR and C57BL͞6 mice displayed the largest and most consistent differences in several different assays of thermal nociception, with AKR being much less sensitive than C57BL͞6. In contrast, AKR mice exhibit more robust heat hyperalgesia after inflammatory or nerve injury (1). Despite our considerable knowledge of the behavioral ''phenomics'' of baseline heat pain and hyperalgesia, there are almost no published data regarding the underlying cellular or molecular mechanisms. Here we show that the observed strain differences in response to thermal stimulation are caused by corresponding differences in the functioning of primary afferent nociceptors. The differences in nociceptor sensitivity, in turn, are caused by the presence of and sensitivity to the neuropeptide calcitonin gene-related polypeptide (CGRP). Finally, linkage mapping revealed a candidate gene likely responsible for the strain difference: Calca, the gene encoding CGRP␣.CGRP␣ is a secretory neuropeptide released from thin nerve fibers at their peripheral and central terminals, which is thought to contribute importantly to neurogenic inflammation in the skin and to central sensitization in the spinal cord (3-6). CGRP acts through a G s protein-coupled receptor complex to activate cAMPdependent protein kinase (PKA). PKA, via the transcription factor cAMP response element-binding protein, enhances expression of pronociceptive genes including the Calca gene itself (7-9). Moreover, many...

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“…Earlier studies noted that substance P did not activate C-fibers to any great extent or sensitize C-fibers to other stimuli using in vitro approaches (Cohen and Perl, 1990;Kessler et al, 1992). Substance P receptors, however, are present on sensory afferent nerve terminals , and local injection of substance P into the hindpaw produces hyperalgesia, allodynia and augmentation of the pain-facilitating actions of glutamate (Nakamura-Craig and Gill, 1991;, which does suggest a contribution to afferent pain signaling by actions on nerve terminals. Substance P also increases vascular permeability, attracts white blood cells, activates phagocytic activity, and increases production and release of inflammatory mediators in neutrophils and macrophages (Levine et al, 1993;Brain, 1996).…”

Section: Neuropeptidesmentioning

confidence: 95%

Topical and Peripherally Acting Analgesics

2003

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Effect of neurokinin A, substance P and calcitonin gene related peptide in peripheral hyperalgesia in the rat paw

Cited by 79 publications

References 14 publications

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

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

Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene

Topical and Peripherally Acting Analgesics

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