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It is known that calcitonin gene-related peptide (CGRP) plays a key role in pain modulation in the brain. There are high expressions of CGRP and CGRP receptor in anterior cingulate cortex (ACC), an important brain structure in pain modulation. The present study explored the role and mechanisms of CGRP and CGRP receptor in nociceptive modulation in ACC in naïve rats and inflammatory rats. Administration of different does of CGRP in ACC induced significant antinociception in a dose-dependent manner in both naïve rats and rats with inflammatory pain. The CGRP-induced antinociception was attenuated by injection of the CGRP receptor antagonist CGRP8-37 in ACC. Interestingly, both CGRP-induced antinociception and CGRP receptor expression decreased in ACC in rats with inflammatory pain compared with naïve rats. Knockdown of CGRP receptor in ACC by siRNA targeting to CGRP receptor attenuated both the CGRP receptor expression and the CGRP-induced antinociception significantly in rats. These findings demonstrate that CGRP and CGRP receptor participate in nociceptive modulation in ACC in rats, inhibiting CGRP receptor expression induces decrease in CGRP-induced antinociception in ACC.

It is known that calcitonin gene-related peptide (CGRP) plays a key role in pain modulation in the brain. There are high expressions of CGRP and CGRP receptor in anterior cingulate cortex (ACC), an important brain structure in pain modulation. The present study explored the role and mechanisms of CGRP and CGRP receptor in nociceptive modulation in ACC in naïve rats and inflammatory rats. Administration of different does of CGRP in ACC induced significant antinociception in a dose-dependent manner in both naïve rats and rats with inflammatory pain. The CGRP-induced antinociception was attenuated by injection of the CGRP receptor antagonist CGRP8-37 in ACC. Interestingly, both CGRP-induced antinociception and CGRP receptor expression decreased in ACC in rats with inflammatory pain compared with naïve rats. Knockdown of CGRP receptor in ACC by siRNA targeting to CGRP receptor attenuated both the CGRP receptor expression and the CGRP-induced antinociception significantly in rats. These findings demonstrate that CGRP and CGRP receptor participate in nociceptive modulation in ACC in rats, inhibiting CGRP receptor expression induces decrease in CGRP-induced antinociception in ACC. [ABSTRACT FROM AUTHOR]

Heat stroke often leads to multiple organ dysfunction syndrome (MODS) with a neurological morbidity of 30%. Current studies suggested that pathophysiological responses to heat stroke may be due to a systemic inflammatory response syndrome and a series of peptidergic nerve reactions. The mechanisms underlying the high neurological morbidity in heat stroke have remained largely elusive. In recent years, calcitonin gene-related peptide (CGRP) has been considered to have a positive role in central nervous system injury. The present study investigated the influence of CGRP on brain injury induced by heat stroke. A rat model of heat stroke was established in a pre-warmed artificial climate chamber with a temperature of 35.5±0.5˚C and a relative humidity of 60±5%. The rectal core temperature (Tc) was monitored. Heat stress was halted at a Tc of no more than 41˚C A bolus injection of CGRP was administered to each rat in the HS+CGRP group and a bolus injection of CGRP8-37 was administered to each rat in the HS+CGRP8-37 group after heat stress. After 2 h, electroencephalograms were recorded and the pathological morphology of brain tissue as well as brain cell apoptosis and caspase-3 protein levels in the brain were measured. The EEG of rats in the HS+CGRP group was characterized by a short- to long-term α-wave and low-voltage β-waves as well as a large amount of intermittent δ- and θ-waves. Compared with the HS group, the θ-wave decreased and the α-wave increased significantly (P<0.05). Slight pathological damage of nerve cells appeared in the HS+CGRP group. Greater damage was observed in HS+CGRP8-37 group with neural cell shrinkage, volume reduction, nuclear pyknosis, disappearance of part of the nuclear membrane and cell necrosis. In the HS+CGRP group, apoptotic cells and caspase-3 protein in the brain were significantly decreased when compared with those in the HS group (P<0.05), while they were significantly increased in the HS+CGRP8-37 group (P<0.05 vs. HS group). The results of the present study reflected that CGRP has a protective effect on early-stage brain injury induced by heat stroke in rats. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the expression of calcitonin gene–related peptide (CGRP) and its role in the liver regeneration process after 70% hepatectomy (Hx). Materials and methods: Wistar rats were divided into eight groups based on time after Hx. Remnant liver samples were collected serially 0 h, 1 h, 6 h, 12 h, 1 d, 2 d, 7 d, and 14 d after Hx (n = 6 for each time point). The expression level of the calcitonin/CGRP gene in the remnant liver was measured. Western bolts and immunohistochemistry were performed to determine the levels of CGRP in the regenerating liver. Furthermore, CGRP8-37 (a CGRP receptor antagonist) was used to examine the role of CGRP during liver regeneration. Results: A marked upregulation of the calcitonin/CGRP gene was observed immediately after Hx, and the protein levels of CGRP in the liver, which were measured by western blot and immunohistochemistry, also rapidly increased after Hx. The liver regeneration rate was significantly attenuated by an administration of CGRP8-37 2 d after Hx. The mitotic index was evaluated by histologic examination 1 and 2 d after Hx and was also significantly lower in the CGRP8-37 group. In addition, CGRP8-37 treatment inhibited the phosphorylation of extracellular-signal regulated kinase 1/2. The levels of early response genes, such as c-fos, c-jun, and c-myc, were also downregulated by CGRP8-37. Conclusion: The calcitonin/CGRP gene may have an important role in the early phase of liver regeneration after Hx. [Copyright &y& Elsevier]

Abstract: Ischemic stroke is a medical emergency triggered by a rapid reduction in blood supply to localized portions of the brain, usually because of thrombosis or embolism, which leads to neuronal dysfunction and death in the affected brain areas. Leptin is generally considered to be a strong and quick stress mediator after injuries. However, whether and how peripherally administered leptin performs neuroprotective potency in cerebral stroke has not been fully investigated. It has been reported that CGRP8-37, an antagonist of the CGRP receptor, could reverse the protective effect of leptin on rats with CIP (caerulein-induced pancreatitis). However, the question remains: are leptin and CGRP associated in cerebral ischemia/reperfusion injury? The present study attempted to evaluate the relationship between CGRP expression and leptin neuroprotective effects (1mg/kg in 200μL normal saline, i.p.) on focal cerebral ischemia/reperfusion injury in mice and the protective effect of leptin (500μg/L) on neurons during hypoxia/reoxygenation injury. Peripheral administration of leptin alleviated injury-evoked brain damage by promoting CGRP expression, improving regional cerebral blood flow, and reducing local infarct volume and neurological deficits. Furthermore, leptin also promoted bcl-2 expression and suppressed caspase-3 in vivo and vitro after injury. Administration of CGRP8-37 (4×10−8 mol/L) partly abolished the beneficial effects of leptin, and restored the normal expression levels of bcl-2 and caspase-3 in neurons, which indicated that leptin-induced protection of neurons was correlated with release of CGRP. These results indicate that the neuroprotective effect of leptin against cerebral ischemia/reperfusion injury may be strongly relevant to the increase of CGRP expression. [Copyright &y& Elsevier]

Abstract: Calcitonin gene-related peptide (CGRP) is a 37 amino-acid peptide, which is widely distributed in peripheral and central nervous system. There are two types of CGRP receptors, CGRP receptor 1 and CGRP receptor 2. It is known that CGRP plays important roles in multiple physiological processes. Studies demonstrate that CGRP and CGRP receptors are involved in the transmission and modulation of pain information in peripheral and central nervous system. CGRP8-37, a specific antagonist for CGRP receptor 1, is widely used to differentiate the two typical CGRP receptors. There are two ambiguous points about the effects of CGRP and CGRP8-37 on pain-related behavioral responses. The first is the effects of exogenous CGRP and CGRP8-37 on the transmission and regulation of pain information in the spinal cord. The second is the effects of these peptides in pain modulation at super-spinal levels. The specific goal of this review is to summarize the roles of CGRP, CGRP8-37 and CGRP receptors in pain-related behavioral responses in the central nervous system. [Copyright &y& Elsevier]

Abstract: The present study was performed to investigate the role of calcitonin gene-related peptide (CGRP) and its receptor in nociception in the basolateral nucleus of amygdala (BLA) of rats. Hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations were measured by hot plate and Randall Selitto tests. The HWL to both thermal and mechanical stimulations increased significantly after intra-BLA administration of 1.0 or 2.0nmol CGRP, but not 0.5nmol, indicating that CGRP plays an anti-nociceptive role in BLA of rats. The anti-nociceptive effect of 1.0nmol CGRP was blocked significantly by administration of 1.0 or 2.0nmol CGRP8-37, a selective antagonist of CGRP1 receptor, which suggests that the anti-nociceptive effect of CGRP is mediated by the CGRP1 receptor. Taken together, the results indicate that both CGRP and CGRP1 receptor play important roles in nociceptive modulation in the BLA of rats. [Copyright &y& Elsevier]

Abstract: Recently, it has been suggested that uninjured primary sensory neurons contribute to neuropathic pain induced by peripheral nerve injury. However, there is lack of evidences of roles of normal pain transmitting substances such as substance P and calcitonin gene-related peptide (CGRP) in neuropathic pain. Whether substance P and CGRP have a role in spinal nerve-injured neuropathic pain model was tested. Male rats were subjected to L5 and L6 spinal nerve transection (SNT), and mechanical hyperalgesia was evaluated by measuring paw withdrawal threshold (PWT). SNT induced a persistent PWT decrease, a sign of neuropathic pain. Lidocaine was soaked on spinal nerves or intrathecally injected 10min before SNT to block neuronal discharges caused by the injury, and L703,606 (NK1 receptor antagonist) and CGRP8-37 (CGRP receptor antagonist) were intrathecally injected into the rats to block actions of substance P and CGRP released from central nerve terminals in the spinal cord by injury discharges. The treatments with lidocaine, L703,606 and CGRP8-37 delayed the onset of neuropathic pain by 1–4 days, compared with the saline-treated rats. After neuropathic pain was established, intrathecal injections of L703,606 and CGRP8-37 significantly mitigated mechanical hyperalgesia for 20min. These results suggest that substance P and CGRP are involved in the development and maintenance of neuropathic pain and that these peptides from the central terminals of intact sensory neurons contribute to the maintenance of peripheral nerve injury-induced neuropathic pain. [Copyright &y& Elsevier]

Background and purpose:A new concept for the inhibition of CGRP signalling has been developed by interaction with the CGRP molecule per se by using a CGRP antibody or a CGRP binding RNA-Spiegelmer (NOX-C89). We have compared these CGRP scavengers with two known receptor antagonists (CGRP8–37 and BIBN4096BS) on CGRP-induced relaxations in the rat middle cerebral artery (MCA). Furthermore, the role of the endothelial barrier has been studied.Experimental approach:We used the luminally perfused MCA in an arteriograph, pressurized to 85 mm Hg and myograph studies of isolated ring segments of the MCA.Key results:In myograph studies and in the perfusion system during abluminal application, αCGRP and βCGRP induced concentration-dependent dilatation of the MCA. Given luminally neither peptide was significantly vasodilator. Adrenomedullin and amylin induced weak dilatations. In myograph experiments, relaxation induced by αCGRP was prevented by the four CGRP blockers (CGRP8–37, BIBN4096BS, the CGRP antibody and NOX-C89.). In abluminal perfusion experiments, the relaxant response to αCGRP was prevented by these agents to a varying degree. Dilatation induced by abluminal application of αCGRP was inhibited by luminal CGRP8–37 but not by luminal BIBN4096BS, CGRP antibody or NOX-C89.Conclusions and Implications:α or βCGRP acted on smooth muscle cell CGRP receptors in rat MCA and were effectively prevented from reaching these receptors by the endothelial barrier. The CGRP blockers significantly inhibited αCGRP induced relaxation but were also prevented from reaching the CGRP receptors by the arterial endothelium.British Journal of Pharmacology (2007) 150, 633–640. doi:10.1038/sj.bjp.0707134; published online 22 January 2007 [ABSTRACT FROM AUTHOR]

Abstract: The physiological significance of calcitonin gene-related peptide (CGRP) during biomineralization was investigated by assessing the effect of human CGRP on the carbonic anhydrase activity in gill membranes of the pearl oyster, Pinctada margaritifera. Salmon CT and human CGRP were able to induce a 150% increase of the basal activity. No additive effect was observed suggesting that both activities are mediated by the same receptor. The CGRP-stimulated effect was specific as demonstrated by the inhibition produced by the CGRP antagonist, hCGRP8-37. So, CGRP by its specific action on gill carbonic anhydrase controls the calcification process, an ancient role both in invertebrates and non-mammalian vertebrates. [Copyright &y& Elsevier]

Abstract: The effects of intravenous (iv) adrenomedullin (AM) on gastric emptying were investigated in conscious rats. AM induced a maximal 50% inhibition of gastric emptying at a dose of 1.2nmol/kg. AM was about two-fold less potent than α-calcitonin gene-related peptide (α-CGRP), which induced a similar 50% maximal inhibition of gastric emptying at 0.6nmol/kg. Delayed gastric emptying induced by i.v. AM and α-CGRP was prevented by peripheral injection of the selective CGRP1 antagonist, CGRP8–37, and by pretreatment with indomethacin, while not altered by blockade of the sympathetic nervous system with propranolol. These data indicate that peripheral AM inhibits gastric emptying through the interaction with CGRP8–37-sensitive receptors, likely CGRP1 receptors, and the recruitment of prostaglandin-dependent mechanisms. [Copyright &y& Elsevier]

We hypothesize that dilatation of extracranial arteries during migraine could be caused by CGRP. We compared the relaxant effects of α-calcitonin gene-related peptide (α-CGRP) and β-calcitonin gene-related peptide (β-CGRP) and the antagonism by BIBN4096BS and CGRP8-37 on rings of human temporal and occipital arteries precontracted with KCl. β-CGRP relaxed temporal (−logEC50M=8.1) and occipital arteries (−logEC50M=7.6) with 19-fold and 29-fold lower potencies respectively than α-CGRP. Nearly maximal effective concentrations of α-CGRP (4 nM) and β-CGRP (50 nM) caused stable relaxations of the temporal artery for 4 h without fading. BIBN4094BS antagonized the effects of α-CGRP (p KB=10.1 and 9.9, respectively) more than β-CGRP (p KB=9.3 and 9.2 respectively) on both temporal and occipital arteries. CGRP8-37 antagonized the effects of α-CGRP (p KB=6.6 and 6.4 respectively) more than β-CGRP (p KB=5.7 and 5.5 respectively) on both temporal and occipital arteries. Antagonism of the relaxant effects of α-CGRP (4 nM) and β-CGRP (50 nM) by BIBN4096BS (10 and 100 nM) was reversible for β-CGRP, but irreversible for α-CGRP, 1 h after BIBN4096BS washout. We conclude that α-CGRP and β-CGRP interact either at different binding sites of the same CGRP receptor system or all together with different receptor systems in human extracranial arteries. BIBN4096BS binds more firmly to the receptor activated by α-CGRP than to the receptor activated by β-CGRP. [ABSTRACT FROM AUTHOR]

Historically, CGRP receptors have been classified as CGRP1 or CGRP2 subtypes, chiefly depending on their affinity for the antagonist CGRP8–37. It has been shown that the complex between calcitonin receptor-like receptor (CRLR or CL) and receptor activity modifying protein (RAMP) 1 provides a molecular correlate for the CGRP1 receptor; however, this does not explain the range of affinities seen for CGRP8–37 in isolated tissues. It is suggested that these may largely be explained by a combination of methodological factors and CGRP-responsive receptors generated by CL and RAMP2 or RAMP3 and complexes of RAMPs with the calcitonin receptor. [Copyright &y& Elsevier]

Ultraviolet (UV) light is an effective treatment for skin disorders like psoriasis in which the cutaneous neurosensory system may have a pathogenic role. In this study, we examined the possibility that UV modulation of the cutaneous neurosensory system and calcitonin generelated peptide (CGRP) may contribute to local immunosuppression mediated by repeated subinflammatory UV irradiation. Our results indicated that exposure of hairless mice to subinflammatory UV three times weekly for 4weeks significantly increased the number of epidermal nerve fibers (ENFs) immunoreactive for CGRP without altering the total number of ENFs. The skin content of CGRP as measured by enzymelinked immunosorbent assay was also significantly increased after exposure to this dose of UV. These effects were most apparent 1 day after the last UV exposure and declined 1week after UV. The role of CGRP in UV-induced immunosuppression of contact hypersensitivity was then examined. Our results indicated that UV suppression of epicutaneous 2,4-dinitro-1-fluorobenzene (DNFB) sensitization could be significantly inhibited by a systemically administered CGRP receptor antagonist. Abr oad-spectrum sunscreen applied before UV exposure inhibited increased cutaneous CGRP and blocked immunosuppression. These findings support a role for CGRP in the local immunosuppression caused by chronic, repeated subinflammatory UV exposure. [ABSTRACT FROM AUTHOR]

Adrenomedullin (AM) has two specific receptors formed by the calcitonin-receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3. These are known as AM1 and AM2 receptors, respectively. In addition, AM has appreciable affinity for the CGRP1 receptor, composed of CL and RAMP1. The AM1 receptor has a high degree of selectivity for AM over CGRP and other peptides, and AM22–52 is an effective antagonist at this receptor. By contrast, the AM2 receptor shows less specificity for AM, having appreciable affinity for βCGRP. Here, CGRP8–37 is either equipotent or more effective as an antagonist than AM22–52, depending on the species from which the receptor components are derived. Thus, under the appropriate circumstances it seems that βCGRP might be able to activate both CGRP1 and AM2 receptors and AM could activate both AM1 and AM2 receptors as well as CGRP1 receptors. Current peptide antagonists are not sufficiently selective to discriminate between these three receptors. The CGRP-selectivity of RAMP1 and RAMP3 may be conferred by a putative disulfide bond from the N-terminus to the middle of the extracellular domain of these molecules. This is not present in RAMP2. [ABSTRACT FROM AUTHOR]

The present study investigated the role of calcitonin gene-related peptide (CGRP) in the modulation of nociception in periaqueductal grey (PAG) of rats. Hindpaw withdrawal latencies (HWLs) were tested by hot-plate and Randall Selitto tests. The HWLs to thermal and mechanical stimulation increased significantly after intra-PAG administration of 0.26 or 0.13 nmol of CGRP, but not 0.026 nmol of CGRP. The anti-nociceptive effects induced by CGRP were significantly blocked by intra-PAG administration of 0.026 or 0.26 nmol of the CGRP1 receptor antagonist CGRP8-37. Furthermore, administration of CGRP into the decussation of superior cerebellar peduncle, out of PAG, did not elicit anti-nociceptive effects during 60 min after the injection. The results demonstrated that CGRP plays an important role in anti-nociception in PAG of rats, and CGRP1 receptor is involved in the CGRP-induced anti-nociception. [Copyright &y& Elsevier]

Adrenomedullin prevents damage of gastric mucosa in either reserpine-treated or pylorus-ligated rats. Pre-treatment with CGRP8–37 resulted in a decrease of the gastro-protective effect of adrenomedullin in both models and reversed the inhibitory effect of adrenomedullin on gastric acid output in the pylorus-ligated rats. These adrenomedullin actions were less effectively modified by pre-treatment with adrenomedullin22–52. These data suggest that the anti-ulcer effect of adrenomedullin is mainly related to its anti-secretory action, presumably mediated through CGRP-receptors. [Copyright &y& Elsevier]

• The administration bolus dose of CGRP-37 and EM-1 can reduce the pain caused by SCI. • Seven day administration of CGRP-37 and EM-1 was not effective for neuropathic pain reduction. • Seven day administration of EM-1 +CGRP-37 compared to monotherapy could not reduce pain. • The combination of EM-1 +CGRP-37 after 7 days injection increased Sigma-1 receptor and SOD and GPx activity. Spinal cord injury is one of the most common causes of neuropathic pain which is not responsive to common treatments. Owing to the adverse effects of drugs, it seems that the use of Calcitonin Gene-Related Protein (CGRP) receptor antagonist or Morphine and their combination could be an appropriate strategy for pain alleviation. To achieve the objective, fifty six male Wistar rats were divided into seven groups. CGRP8-37 and Endomorphin-1 alone, and in combinated administration, as bolus and continues dose. Both mechanical and cold allodynia, and mechanical hyperalgesia were evaluated before and also15 and 60 min after injection to indicate the efficacy of the therapies in the acute and chronic circumstances on pain induced by spinal cord compression injury. Sigma-1 receptor experssion, oxidant and antioxidant activity after the seven days of the drug adminestration were evaluated. The results showed that Endomorphin-1and CGRP8-37 injections were able to reduce neuropathic pain after spinal cord compression injury. Compared to Endomorphin-1, or CGRP8-37 monotherapy, combination therapy did not show more attenuating effects on the pain threshold. Compared to the continous administration of Endomorphin-1 alone, and CGRP8-37 alone, the continous combination therapy did not reduce the pain further. Molecular studies disclosed the increased expression of the Sigma1 receptor, in the spinal cord after administration of Endomorphin-1, and CGRP8-37 alone, as well as combination therapy. Although, an increase in GPx and SOD activity, and decrease in MDA activity was observed in the combination therapy. Our results demonstrate that either Endomorphin-1 or CGRP receptor antagonist is able to decrease the neuropathic pain after SCI but combination therapy by a CGRP receptor antagonist and Endomorphin-1 did not make any further reduction in pain sensation. [ABSTRACT FROM AUTHOR]