Calcitonin Gene-Related Peptide: Physiology and Pathophysiology

Abstract

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

“…The sensitivity to pain and injury severity is also evident in spinal CGRP expression (Fig. 5), which also increases after a host of painful peripheral traumas and inflammatory stimuli [18,50,56,69,92]. In contrast, it decreases after a painful root compression [37,92], most likely from axonal degeneration in the root decreasing trafficking to the dorsal horn.…”

“…Because CGRP enhances PKC-mediated signaling to increase neuronal hyperexcitability [44,58,74] and because only peripheral PKCe is upregulated after nonpainful 15 Hz WBV, it is likely that several responses sustain pain from WBV. CGRP is also proinflammatory in the dorsal horn, recruiting immune cells [15,69] and modulating cytokine release [69].…”

“…PKCe is responsible for heat and pain sensitivity in peripheral nociceptors [16,93] and, through PKC pathway signaling, also modulates spinal calcitonin gene-related peptide (CGRP) activity [69,74]. After injury, CGRP is released by nociceptive fibers in the superficial dorsal horn [56,58,74,76] and can stimulate spinal immune cell activation [15,64] and cytokine release [69].…”

Migraine and Obesity: Possible Link to Inflammation

“…the trigeminal ganglia, the cortex, and the pituitary gland) and in white adipose tissue (WAT) (adipocytes, pre-adipocytes) [36][37][38]. Elevated levels of CGRP in migraine is explained by electrical stimulation of the TG of nerves, the release of CGRP and other peptides cause an increase in cerebral blood fluid, dilation of the cerebral vessels and the local release of pro-inflammatory mediators [39][40].…”

Proof-of-Principle, Open-Label Prospective Cohort Trial of a Novel Nutraceutical for the Prevention of Refractory Migraine

“…This peptide is a potent vasodilatator and can function in the transmission of pain. Its implication in the pathogenesis of migraine [13] may lead to the development of antagonists that may be used as new therapeutic agents for migraine [14]. At the other hand, proton ((1)H) and phosphorus ((31)P) magnetic resonance spectroscopy has revealed major reduction of high-energy phosphates production in the occipital lobe of migrainewithout-aura patients [15][16][17], suggesting the presence of a mitochondrial component in the physiopathology.…”