Roles of calcitonin gene-related peptide and its receptors in pain-related behavioral responses in the central nervous system

Yu, Long-Chuan; Hou, Jingbo; Fu, Fenghua; Zhang, Yingxin

doi:10.1016/j.neubiorev.2009.03.009

Cited by 54 publications

(45 citation statements)

References 68 publications

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“…It was reported that intrathecal administration of CGRP 8-37 induced very strong inhibition on the pain-related responses to thermal and mechanical noxious stimulations in rats, indicating that CGRP 8-37 induced strong analgesic effects in the spinal cord (45)(46)(47). The present study has shown that the CGRP antagonist is also effective against inflammatory pain in-…”

Section: Discussionsupporting

confidence: 65%

Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats

et al. 2011

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Histamine and calcitonin gene-related peptide (CGRP) contribute to the pain perception. The aim of the present study is to clarify the interaction of histamine and CGRP in the perception of inflammatory pain. The effects of a histamine H1 receptor antagonist (pyrilamine, i.p.), an H2 receptor antagonist (ranitidine, i.p.) and a CGRP antagonist (CGRP 8-37, i.t.) on the formalininduced pain was studied in rats. Pyrilamine and ranitidine produced a dose-dependent antinociceptive response in the first and the second phases of the formalin test. A single administration of pyrilamine (1 mg/kg, i.p.), ranitidine (10 mg/kg, i.p.) or CGRP 8-37 (10 μg/μL, i.t.) had no significant effects on the pain perception in the second phase. A combination of CGRP 8-37 and pyrilamine or ranitidine at these sub-effective doses, however, showed nociceptive response in the second phase. Moreover, a histamine (i.t.)-induced hyperalgesia was completely prevented by treatment with GGRP 8-37 at this dose. Our findings have raised the possibility that the CGRP system has interaction with histamine in the perception of inflammatory pain.Pain perception is modulated in the spinal cord by many bioactive substances, such as histamine (38, 39), substance P and calcitonin gene-related peptide (CGRP) (12, 28). Histamine is mostly derived from two cell types, neurons and mast cells. The cell bodies of histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus (15). The descending histaminergic neurons terminate at the periaqueductal gray and the dorsal horn of the spinal cord (30,31,43), which is an important site for nociceptive transmission (2). All three histamine H1, H2 and H3 receptors (16) are found in the dorsal horn (26,33,42) and play important roles in the pain perception (22)(23)(24)(25). CGRP is a 37-amino-acid neuropeptide widely distributed in the peripheral and central nervous systems including the dorsal root ganglion (DRG) and its primary afferent terminals in the spinal cord (1, 37). The actions mediated by CGRP type 1 receptor, which is considered to consist of calcitonin receptor-like receptor and receptor activity modifying protein-1 (21), is antagonized by CGRP 8-37 (8). CGRP and its receptors are involved in many stages of pain neurotransmission, especially in the spinal cord (12, 28). As a neurotransmitter, CGRP itself had no obvious effect in pain modulation, but potentiated the excitatory effect induced by substance P or other nociceptive stimuli in the dorsal horn of the spinal cord (3). CGRP stimulated histamine release from mast cells and potentiated histamine ac-

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Section: Discussionsupporting

confidence: 65%

Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats

et al. 2011

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“…13,24 The observation that intrathecal administration of CGRP increases the activity of WDR neurons further supports a role of CGRP and CGRP receptors in driving central sensitization in CIBP. 48 Furthermore, our evidence suggests that neurons are not the only cells mediating the effect of CGRP. Specifically, we observed that reactive astrocytes in the dorsal horn ipsilateral to the cancer-bearing bone expressed CGRP receptors (CLR/ RAMP1).…”

Section: Discussionmentioning

confidence: 74%

Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain

Hansen

Vacca

Pitcher

et al. 2016

Pain

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Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (α-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP.

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“…Glutamate is the major neurotransmitter released by nociceptors, but many nociceptive neurons also contain neuropeptide co-transmitters that help to transmit and modulate nociceptive inputs. Calcitonin gene-related peptide (CGRP) and substance P (SP) are the main neuropeptides that are expressed by an important subset of nociceptors that innervate skin and viscera [51]. Embryonic nociceptors contain no detectable CGRP mRNA or protein until their axons contact target tissues and the peripheral connections are functional, which indicates that peptidergic phenotype specification in nociceptive neurons is dependent on retrograde signals from targets [52,53].…”

Section: Activin and Bmp Retrograde Signals Modulate The Expression Omentioning

confidence: 99%

Transforming Growth Factor-β in Normal Nociceptive Processing and Pathological Pain Models

et al. 2011

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The transforming growth factor-β (TGF-β) superfamily is a multifunctional, contextually acting family of cytokines that participate in the regulation of development, disease and tissue repair in the nervous system. The TGF-β family is composed of several members, including TGF-βs, bone morphogenetic proteins (BMPs) and activins. In this review, we discuss recent findings that suggest TGF-β function as important pleiotropic modulators of nociceptive processing both physiologically and under pathological painful conditions. The strategy of increasing TGF-β signaling by deleting "BMP and activin membrane-bound inhibitor" (BAMBI), a TGF-β pseudoreceptor, has demonstrated the inhibitory role of TGF-β signaling pathways in normal nociception and in inflammatory and neuropathic pain models. In particular, strong evidence suggests that TGF-β1 is a relevant mediator of nociception and has protective effects against the development of chronic neuropathic pain by inhibiting the neuroimmune responses of neurons and glia and promoting the expression of endogenous opioids within the spinal cord. In the peripheral nervous system, activins and BMPs function as target-derived differentiation factors that determine and maintain the phenotypic identity and circuit assembly of peptidergic nociceptors. In this context, activin is involved in the complex events of neuroinflammation that modulate the expression of pain during wound healing. These findings have provided new insights into the physiopathology of nociception. Moreover, specific members of the TGF-β family and their signaling effectors and modulator molecules may be promising molecular targets for novel therapeutic agents for pain management.

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Roles of calcitonin gene-related peptide and its receptors in pain-related behavioral responses in the central nervous system

Cited by 54 publications

References 68 publications

Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats

Interaction of histamine and calcitonin gene-related peptide in the formalininduced pain perception in rats

Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain

Transforming Growth Factor-β in Normal Nociceptive Processing and Pathological Pain Models

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