Calcitonin gene-related peptide, neurokinin A and substance P: Effects on Nociception and neurogenic inflammation in human skin and temporal muscle

Pedersen‐Bjergaard, Ulrik; Nielsen, Lars B.; Jensen, Kai; Edvinsson, Lars; Jansen, I.; Olesen, Jes

doi:10.1016/0196-9781(91)90022-h

Cited by 123 publications

(69 citation statements)

References 27 publications

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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: 87%

“…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.…”

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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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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

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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show abstract

“…Besides transmitting pain, the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP), which are present in such nerves, have efferent effects. These effects include vasodilation and plasma extravasation, leading to so-called neurogenic inflammation [Foreman, 1987;Pedersen-Bjergaard et al, 1991;Wiesenfeld-Hallin and Xu, 1993]. Various joint tissues, such as knee ligaments and joint capsules, are supplied with a sensory innervation and it has therefore been suggested that these structures are susceptible to neurogenic inflammation [Scott et al, 1994;McDougall et al, 1997], whilst others like the coracoacromial ligament [Konttinen et al, 1992] and ligementum flavum [Ashton et al, 1992] are devoid of innervation.…”

Section: Introductionmentioning

confidence: 99%

Sympathetic and Sensory Innervations Are Heterogeneously Distributed in Relation to the Blood Vessels at the Extensor carpi radialis brevis Muscle Origin of Man

Ljung

Forsgren

Fridén³

1999

Cells Tissues Organs

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By using immunohistochemistry and antibodies to a general nerve marker, protein gene product (PGP) 9.5, the overall innervation at the extensor carpi radialis brevis (ECRB) muscle origin was investigated in patients with tennis elbow and in healthy controls. The autonomic innervation was studied by using antibodies to neuropeptide Y (NPY), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP). The sensory innervation was visualized by using antibodies to substance P and calcitonin gene-related peptide. PGP 9.5 immunoreactions were detected in association with small blood vessels and arteries and within nerve bundles. There was, however, heterogeneity in the perivascular nerve fiber distribution since some blood vessels exhibited a high degree of PGP 9.5 innervation and some negligible or no such innervation at all. There was marked TH/NPY innervation in the walls of a subpopulation of the arteries, basically no VIP-containing nerves, and sensory innervation restricted to the small blood vessels. These observations show that the ECRB muscle origin is supplied with heterogeneously distributed sympathetic and sensory innervations and, furthermore, that there appears to be an imbalance between the vasoconstrictor and vasodilator innervations along the vascular tree in this region.

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“…Apart from transmitting nociceptive information to the spinal cord, sensory nerves have efferent effects [47]. These include vasodilation and plasma extravasation, effects particularly transmitted by the neuropeptides substance P (SP) and calcitonin generelated peptide (CGRP) and that might lead to so-called neurogenic inflammation [13,15,37,47]. Some parts of the locomotor system have been extensively investigated with respect to the occurrence of sensory innervation.…”

Section: Introductionmentioning

confidence: 99%

Neurokinin 1‐receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus Studies on tennis elbow and medial epicondylalgia

Ljung

Alfredson

Forsgren

2004

Journal Orthopaedic Research

130

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There is no information on the sensory innervation at the flexor muscle origin at the medial epicondyle of the humerus and it is not known if substance P receptors (Neurokinin I-receptors, NKI-R) are present in tendon insertions in general. In the present investigation, we have studied the muscle origin in patients suffering from medial epicondylalgia and tennis elbow. Immunohistochemistry and antibodies to substance P (SP) and CGRP as well as the general nerve marker PGP 9.5 were used. Specific immunoreactions were observed in nerve bundles and as free nerve fibers. The immunoreactive structures were partly seen in association with some of the blood vessels. The observations constitute a morphological correlate for the occurrence of nerve mediated effects in this region. By using immunohistochemistry and antibodies to NKI-R, the distribution of this receptor was studied at the insertion of the proximal tendon of the extensor carpi radialis brevis muscle at the lateral epicondyle. Specific immunoreactions were seen as varicose fibers occurring as single fibers or grouped into bundles, indicating that SP has effects in the nerves in this region. The results give further evidence for a possible neurogenic involvement in the pathophysiology of tennis elbow and in medial epicondylalgia.

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Calcitonin gene-related peptide, neurokinin A and substance P: Effects on Nociception and neurogenic inflammation in human skin and temporal muscle

Cited by 123 publications

References 27 publications

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

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

Sympathetic and Sensory Innervations Are Heterogeneously Distributed in Relation to the Blood Vessels at the Extensor carpi radialis brevis Muscle Origin of Man

Neurokinin 1‐receptors and sensory neuropeptides in tendon insertions at the medial and lateral epicondyles of the humerus Studies on tennis elbow and medial epicondylalgia

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