Elsevier

Neuroscience Letters

Volume 587, 5 February 2015, Pages 29-34
Neuroscience Letters

Research article
Effects of rizatriptan on the expression of calcitonin gene-related peptide and cholecystokinin in the periaqueductal gray of a rat migraine model

https://doi.org/10.1016/j.neulet.2014.12.021Get rights and content

Highlights

  • Investigate the expression of CGRP and CCK in the PAG during migraine attacks.

  • Assess the influence of rizatriptan on midbrain CGRP and CCK expression.

  • Provide useful insights into how rizatriptan regulates the endogenous pain modulatory system.

Abstract

Triptans are serotonin 5-hydroxytryptamine receptor 1B/D agonists that are highly effective in the treatment of migraine. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system. Calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) are mainly responsible for antagonizing the analgesic effects of opioid peptides in the endogenous pain modulatory system. In this study, we investigated the effects of rizatriptan on the expression of CGRP and CCK in the periaqueductal gray (PAG), a key structure of the endogenous pain modulatory system, in a rat migraine model induced by nitroglycerin. We found that the mRNA and protein levels of CGRP and CCK in the PAG of migraine rats were significantly increased compared to those in control rats, and these levels were significantly reduced upon treatment with rizatriptan in migraine rats (P < 0.05). Our results suggest that the expression of CGRP and CCK in the endogenous pain modulatory system may be increased during migraine attacks, which further antagonizes the analgesic effects of endogenous opioid peptides and induces sustained migraine. Rizatriptan, however, significantly reduces the levels of CGRP and CCK to enhance the inhibition of pain signals via the endogenous pain modulatory system, resulting in effective treatment of migraine.

Introduction

The periaqueductal gray (PAG) is an important structure that plays a central role in the endogenous pain modulatory system because most of the analgesic effects caused by the activation of higher centers have been proven to be achieved only via the PAG [15], [22]. Pain-related neuropeptides such as endogenous opioid peptides, substance P, calcitonin gene-related peptide (CGRP), and cholecystokinin (CCK) are important mediators of the endogenous pain modulatory system and participate in regulating its functions [4], [17]. Endogenous opioid peptides and opioid receptor agonists play a critical role in the central analgesic effect by inhibiting neuronal discharges of pain and activating the descending inhibitory pain modulation system in the brain [17]. Substance P has been found to exert its analgesic effect by inducing the release of encephalin from the PAG [29]. CGRP and CCK in the endogenous pain modulatory system are thought to antagonize the analgesic effect of endogenous opioid peptides [24].

Triptans are serotonin 5-hydroxytryptamine receptor 1B/D (5HT1B/D) agonists that are highly effective in the treatment of migraine. The mechanism of action for triptans is attributed to the constriction of dilated cerebrovascular and brain meningeal blood vessels via their agonist effects on serotonin 5HT1B/D receptors [9], [16]. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system [27]. Rizatriptan has been found to affect the CGRP level in the trigeminal vascular system [5], [19]; however, its effect on the CGRP level in the endogenous pain modulatory system remains unclear. Also, CCK is present in the nervous system, especially in the cerebral regions related to pain modulation [14]. Unfortunately, there has been no studying reporting the effect of rizatriptan on CCK level in the endogenous pain modulatory system. In this study, we established a rat migraine model via induction with nitroglycerin [18] and investigated the effects of rizatriptan on the mRNA and protein levels of CGRP and CCK in the PAG of migraine model rats. Our results provide useful insights into the mechanism by which rizatriptan regulates the endogenous pain modulatory system in the treatment of migraine.

Section snippets

Animals and treatments

Wistar adult rats (24 males and 24 females, body weight of 200–220 g) were obtained from the Laboratory Animal Center at the Jilin University (Changchun, China) [Certificate No.: SCXK(JI):2003-001]. Rats were maintained at a constant temperature (21 ± 1 °C) and humidity (40–70%) with a 12-h light/dark cycle. The animals were given ad libitum access to food and water. All animal-related procedures conformed to the guidance of the care and use of laboratory animals issued by the Ministry of Science

Standard curves for CGRP and CCK using real-time RT–PCR

The linear range of the standard curve for CGRP was 2.7 × 103  2.7 × 109 copies/μl, with a linear regression equation of Ct = −2.69 log(x) + 38.875 (r = 0.993). The linear range of the standard curve for CCK was 2.8 × 103  2.8 × 109 copies/μl, with a linear regression equation of Ct = −1.907 log(x) + 35.224 (r = 0.953). In addition, melting curve analysis revealed a single peak at 88 °C for CGRP and 86 °C for CCK PCR products, indicating the specificity of their PCR products.

Rizatriptan reduces mRNA and protein levels of CGRP in the midbrain of migraine model rats

The cDNA of each midbrain sample and CGRP

Discussion

The endogenous pain modulatory system plays a critical role in the regulation of nociception. However, there have been few studies investigated whether triptans affect the function of the endogenous pain modulatory system in the treatment of migraine. In this study, we established a rat migraine model using nitroglycerin and investigated the effects of rizatriptan on the mRNA and protein levels of CGRP and CCK in the PAG of migraine model rats. Our results provide potentially useful insights

Author contributions

Gang Yao participated in the study concept and design, experimental implementation, data integrity and analysis, and wrote the manuscript. Ximei Han participated in the design of the study, conducted the experiments and performed the data integrity and analysis. Tingting Hao and Qian Huang conducted the experiments. Tingmin Yu participated in the study concept and design and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant No. 31372267), Health and Family Planning Commission Of Jilin Province Project (Grant No. 2013Q020), and the Young Scholar Program of Norman Bethune Health Science Center of Jilin University (Grant No. 2013206044).

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