CGRP in Spinal Cord Pain Mechanisms

Neugebauer, Volker

doi:10.1007/978-1-4419-0226-9_8

Cited by 4 publications

(8 citation statements)

References 87 publications

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“…Relevant to the antiallodynic effect of this antagonist, spinal application of CGRP8-37 can significantly reduce dorsal horn neuron sensitization to innocuous stimuli of peripheral deep tissue in models of knee arthritis. 32 Our data indicate that an increased primary afferent input into the dorsal horn is responsible for allodynia in CIBP. Glutamate drives neuronal activation at the spinal level in CIBP through activation of NMDA receptors, 18,47 an effect that is potentiated by CGRP.…”

Section: Discussionmentioning

confidence: 91%

“…Here, extracellular CGRP can act on CGRP receptors expressed in dorsal horn neurons, which leads to neuronal excitation and facilitation of glutamate receptor (AMPA and NMDA)-mediated responses. 32 We observed that CGRP receptor components were present in higher numbers than under normal conditions and suggest that CGRP may act by enhancing neuronal activation driven by glutamate. 26 In agreement with this possibility, we found that a CGRP receptor antagonist (a-CGRP8-37) injected at the lumbar spinal cord level attenuated bone cancer-induced allodynia.…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 94%

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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“…CGRP in amygdala is thought to play a critical role in migraine pathophysiology, temporomandibular disorders and pain behaviors (Doods et al . ; Neugebauer ). Within the spino‐parabrachio‐amygdala pain pathway, CGRP facilitates synaptic transmission that provides nociceptive information from the parabrachial area to latero‐capsular division of the central nucleus of amygdala (CeLC).…”

Section: Discussionmentioning

confidence: 99%

Calcitonin gene‐related peptide erases the fear memory and facilitates long‐term potentiation in the central nucleus of the amygdala in rats

Zhang

Liu

et al. 2015

Journal of Neurochemistry

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Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide, which plays a critical role in the central nervous system. CGRP binds to G protein-coupled receptors, including CGRP1, which couples positively to adenylyl cyclase (AC) and protein kinase A (PKA) activation. CGRP and CGRP1 receptors are enriched in central nucleus of the amygdala (CeA), the main part of the amygdala, which regulates conditioned fear memories. Here, we reported the importance of CGRP and CGRP1 receptor for synaptic plasticity in the CeA and the extinction of fear memory in rats. Our electrophysiological and behavioral in vitro and in vivo results showed exogenous application of CGRP induced an immediate and lasting longterm potentiation in the basolateral nucleus of amygdala-CeA pathway, but not in the lateral nucleus of amygdala-CeA pathway, while bilateral intra-CeA infusion CGRP (0, 5, 13 and 21 lM/side) dose dependently enhanced fear memory extinction. The effects were blocked by CGRP1 receptor antagonist ), N-methyl-D-aspartate receptors antagonist MK801 and PKA inhibitor H89. These results demonstrate that CGRP can lead to long-term potentiation of basolateral nucleus of amygdala-CeA pathway through a PKA-dependent postsynaptic mechanism that involved N-methyl-D-aspartate receptors and enhance the extinction of fear memory in rats. Together, the results strongly support a pivotal role of CGRP in the synaptic plasticity of CeA and extinction of fear memory. Keywords: calcitonin gene-related peptide, central nucleus of amygdala, fear extinction, long-term potentiation, synaptic plasticity. The neuropeptides play diverse and critical roles in regulating neuronal structures and functions in the central nervous system (Brain and Cox 2006;Sharf et al. 2008;Lyons and Thiele 2010). However, the role of neuropeptides in synaptic plasticity is less well known than that of classical neuronal transmitters, such as glutamate and c-aminobutyric acid (GABA). Calcitonin gene-related peptide (CGRP) is produced by calcitonin gene and expressed throughout the central and peripheral nervous system, especially in the nucleus accumbens, the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), Received February 10, 2015; revised manuscript received May 10, 2015; accepted July 1, 2015. Address correspondence and reprint requests to Dr Fang Wang, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, HUST, Number 13, Hangkong Road, Wuhan, Hubei 430030, China. E-mail: wangfangtj0322@163.com Abbreviations used: ACSF, artificial cerebrospinal fluid; AMPA, alphaamino-3-hydroxy-5-methylisoxazole-4-propionate; BLA, basolateral nucleus of amygdala; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CGRP, calcitonin gene-related peptide; CS, conditioned stimulus; fEPSP, field excitatory postsynaptic potential; LA, lateral nucleus of amygdala; LTP, long-term potentiation; NAc, nucleus accumbens; PFC, prefrontal cortex; US, unconditioned stimulus.

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“…Before each drug application, ACSF was pumped through the fiber for at least 1 h to establish equilibrium in the tissue. Drugs were dissolved in ACSF on the day of the experiment at a concentration 100-fold that predicted to be needed based on data from our previous microdialysis and in vitro studies and data in the literature [5,22,30,45]. Drug concentration in the tissue is at least 100 times lower than in the microdialysis probe as a result of the concentration gradient across the dialysis membrane and diffusion in the tissue [22,30].…”

Section: Methodsmentioning

confidence: 99%

“…CGRP has emerged as an important molecule at different levels of the pain neuraxis [5]. Particularly high levels of CGRP binding sites [1,4,6,7] and proteins required for functional CGRP1 receptors [8,9] have been described in the superficial spinal dorsal horn and in the central nucleus of the amygdala (CeA), where also CGRP containing fibers terminate [4,7,10-13].…”

Section: Introductionmentioning

confidence: 99%

Facilitation of Synaptic Transmission and Pain Responses by CGRP in the Amygdala of Normal Rats

et al. 2010

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Calcitonin gene-related peptide (CGRP) plays an important role in peripheral and central sensitization. CGRP also is a key molecule in the spino-parabrachial-amygdaloid pain pathway. Blockade of CGRP1 receptors in the spinal cord or in the amygdala has antinociceptive effects in different pain models. Here we studied the electrophysiological mechanisms of behavioral effects of CGRP in the amygdala in normal animals without tissue injury.Whole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in rat brain slices showed that CGRP (100 nM) increased excitatory postsynaptic currents (EPSCs) at the parabrachio-amygdaloid (PB-CeLC) synapse, the exclusive source of CGRP in the amygdala. Consistent with a postsynaptic mechanism of action, CGRP increased amplitude, but not frequency, of miniature EPSCs and did not affect paired-pulse facilitation. CGRP also increased neuronal excitability. CGRP-induced synaptic facilitation was reversed by an NMDA receptor antagonist (AP5, 50 μM) or a PKA inhibitor (KT5720, 1 μM), but not by a PKC inhibitor (GF109203X, 1 μM). Stereotaxic administration of CGRP (10 μM, concentration in microdialysis probe) into the CeLC by microdialysis in awake rats increased audible and ultrasonic vocalizations and decreased hindlimb withdrawal thresholds. Behavioral effects of CGRP were largely blocked by KT5720 (100 μM) but not by GF109203X (100 μM).The results show that CGRP in the amygdala exacerbates nocifensive and affective behavioral responses in normal animals through PKA- and NMDA receptor-dependent postsynaptic facilitation. Thus, increased CGRP levels in the amygdala might trigger pain in the absence of tissue injury.

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CGRP in Spinal Cord Pain Mechanisms

Cited by 4 publications

References 87 publications

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

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

Calcitonin gene‐related peptide erases the fear memory and facilitates long‐term potentiation in the central nucleus of the amygdala in rats

Facilitation of Synaptic Transmission and Pain Responses by CGRP in the Amygdala of Normal Rats

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