Elsevier

Neuroscience

Volume 118, Issue 4, 6 June 2003, Pages 1015-1022
Neuroscience

Research paper
Antinociceptive effect of calcitonin gene-related peptide in the central nucleus of amygdala: activating opioid receptors through amygdala–periaqueductal gray pathway

https://doi.org/10.1016/S0306-4522(03)00069-1Get rights and content

Abstract

The central nucleus of amygdala (CeA) plays an important role in pain regulation. Calcitonin gene-related peptide (CGRP)-like immunoreactive fibers and CGRP receptors are distributed densely in CeA. The present study was performed to elucidate the role of CGRP in nociceptive regulation in the CeA of rats. Intra-CeA injection of CGRP induced dose-dependent increases in the hind-paw withdrawal latency tested by hotplate test and Randall Selitto Test, indicating an antinociceptive effect of CGRP in CeA. Furthermore, the antinociceptive effect of CGRP was blocked by intra-CeA administration of the CGRP receptor antagonist CGRP8-37, suggesting that CGRP receptor1 is involved in the CGRP-induced antinociception. The CGRP-induced antinociception was attenuated by s.c. injection of the opioid antagonist naloxone, suggesting an involvement of endogenous opioid systems in CGRP-induced antinociception. Moreover, it was demonstrated that opioid receptors in the periaqueductal gray, but not in CeA, contributed to the CGRP-induced antinociception, indicating the importance of the pathway between CeA and the periaqueductal gray in CGRP-induced antinociception. Combining retrograde fluorescent tracing with immunohistochemistry, we found that met-enkephalinergic neurons were innervated by CGRP-containing terminals in CeA. Furthermore, most neurons in the CeA retrogradely traced from the periaqueductal gray were contacted by CGRP-containing terminals and some of them were surrounded by characteristic basket-like structures formed by the terminals, suggesting that CGRP innervates the neurons which project from CeA to the periaqueductal gray. The results indicate that CGRP activates the met-enkephalinergic neurons, which project from CeA to the periaqueductal gray, producing antinociceptive effect in rats.

Section snippets

Animal preparation and intra-nucleus injections

Male Sprague–Dawley rats (220–250 g; Institute of Zoology, Chinese Academy of Science, Beijing, China) were used. The rats were housed in cages with free access to food and water, and maintained in a room temperature of 24 °C with a 12-h light/dark cycle. Experiments were conducted according to the guidelines of the animal ethical committee of Karolinska Institutet and every effort was made to minimize both the animal suffering and the number of animals used. The animals were anesthetized by

Effects of intra-CeA administration of CGRP on HWLs in rats

Rats received intra-CeA injection of 0.2 (n=7), 1 (n=8) or 2 nmol of CGRP (n=8), or 1 μl of 0.9% saline (n=8) as a control. Compared with the control group, the HWLs increased significantly after intra-CeA injection of 1 (thermal test: F=33.88, P<0.001; Randall Selitto test: F=3.59, P=0.07) or 2 nmol of CGRP (thermal test: F=11.82, P<0.05; Randall Selitto test: F=10.32, P<0.01), but not 0.2 nmol of CGRP (thermal test: F=1.61, P=0.22; Randall Selitto test: F=1.29, P=0.27), as shown in Fig. 1.

Effects of intra-,CeA injection of CGRP8-37 on the CGRP-induced increase in HWLs of rats

The antinociceptive effect of CGRP in the CeA

It has been reported that i.c.v. injection of CGRP induces antinociception Pecile et al 1987, Candeletti and Ferri 1990. Furthermore, studies in our laboratory found that CGRP elicited antinociceptive effects in the nucleus raphe magnus and the PAG of rats Huang et al 2000, Xu et al 2000. The present study demonstrated that intra-CeA administration of CGRP induced antinociception dose-dependently in rats tested by hotplate test and Randall Selitto test. Furthermore, the antinociceptive effect

Acknowledgements

The study was supported by funds from the National Natural Science Foundation of China (NSFC) and the Karolinska Institute Foundation. We are very grateful to Mr. Ju-Shuai Zhang for generously supplying us with Fast Blue and to Miss Qingqing Han and Mr. Yun Zhao for the assistance in processing the microphotographs.

References (41)

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    Electrophysiology experiments in rodents suggest that CGRP drives potentiation in the right CeA by increasing the amplitude of NMDA-mediated EPSCs (Han et al., 2010; Okutsu et al., 2017), most likely through CGRP receptor-driven activation of protein kinase A (PKA) (Han et al., 2005). In another study, pharmacological infusion of CGRP into the left CeA of naïve rats increases mechanical hindlimb threshold (side not specified), suggesting an anti-nociceptive effect (Xu et al., 2003). It is possible that CGRP has different roles in the left and right CeA, or its role could depend on pain modality or chronicity.

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