The effect of intracerebroventricular injection of CGRP on pain behavioral responses and monoamines concentrations in the periaqueductal gray area in rat

Document Type : Original Article

Authors

1 Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Department of Basic Sciences,, School of Medicine, Shiraz University of Medical Sciences, Shiraz,Iran

Abstract

Objective(s): Calcitonin gene related peptide (CGRP) receptors are widely distributed in the central nervous system. The aim of this study was to investigate the effects of intracerebroventricular (ICV) injection of CGRP on pain behavioral responses and on levels of monoamines in the periaqueductal gray area (PAG) during the formalin test in rats.
Materials and Methods: Twenty-four male rats were studied in four groups (n=6). CGRP was injected into the left cerebral ventricle (1.5 nmol, 5 µl). After 20 min, formalin (2.5%) was subcutaneously injected into the right hind paw. Behavior nociceptive score was recorded up to 60 min. During the formalin test, the PAG was subjected to microdialysis and levels of norepinephrine, 3-methoxy-4-hydroxyphenyl-glycol (HMPG), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin and 5-hydroxyindole-acetic acid (HIAA) were measured by HPLC.
Results: ICV injection of CGRP lead to a significant pain reduction in acute, middle and chronic phases of the formalin test. Dialysate concentrations of norepinephrine, HMPG, dopamine, DOPAC, serotonin and HIAA in the PGA area showed an increase in acute phase, middle phase and beginning of the chronic phase of the formalin test.
Conclusion: CGRP significantly reduced pain by increased concentrations of monoamines and their metabolites in dialysates from PAG when injected ICV to rats.

Keywords

Main Subjects

References

1. Vanegas H, Schaible H-G. Descending control of persistent pain: inhibitory or facilitatory? Brain Res Rev 2004; 46:295-309.
2. Fields HL BA, Heinricher MM. Central nervous system mechanisms of pain modulation. In: McMahon S, Koltzenburg M, eds Textbook of Pain Burlington, Massachusetts, USA: Elsevier Health Sciences. 2005;5th ed:125-142.
3. Bourgeais L, Monconduit L, Villanueva L, Bernard JF. Parabrachial internal lateral neurons convey nociceptive messages from the deep laminas of the dorsal horn to the intralaminar thalamus. J Neurosci Res 2001; 21:2159-2165.
4. Bannister K, Dickenson AH. What do monoamines do in pain modulation? Curr Opin Support Palliat Care 2016; 10:143-148.
5. Kwiat GC, Basbaum AI. Organization of tyrosine hydroxylase- and serotonin-immunoreactive brainstem neurons with axon collaterals to the periaqueductal gray and the spinal cord in the rat. Brain Res 1990; 528:83-94.
6. Durham PL, Vause CV. Calcitonin gene-related peptide (CGRP) receptor antagonists in the treatment of migraine. CNS drugs 2010; 24:539-548.
7. Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine pathophysiology. Nat Rev Neurol 2010; 6:573-582.
8. Sexton PM, McKenzie JS, Mendelsohn FA. Evidence for a new subclass of calcitonin/ calcitonin gene-related peptide binding site in rat brain. Neurochem int 1988; 12:323-335.
9. Henke H, Tschopp FA, Fischer JA. Distinct binding sites for calcitonin gene-related peptide and salmon calcitonin in rat central nervous system. Brain Res 1985; 360:165-171.
10. Sexton PM, McKenzie JS, Mason RT, Moseley JM, Martin TJ, Mendelsohn FA. Localization of binding sites for calcitonin gene-related peptide in rat brain by in vitro autoradiography. J Neurosci Res 1986; 19:1235-1245.
11. Kruger L, Mantyh PW, Sternini C, Brecha NC, Mantyh CR. Calcitonin gene-related peptide (CGRP) in the rat central nervous system: patterns of immunoreactivity and receptor binding sites. Brain Res 1988; 463:223-244.
12. Sexton PM. Central nervous system binding sites for calcitonin and calcitonin gene-related peptide. Mol Neurobiol 1991; 5:251-273.
13. Walker CS, Hay DL. CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? Br J Pharmacol 2013; 170:1293-1307.
14. Pozo-Rosich P, Storer RJ, Charbit AR, Goadsby PJ. Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia: Cephalalgia 2015; 35:1298-1307.
15. Storer RJ, Akerman S, Goadsby PJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br j pharmacol 2004; 142:1171-1181.
16. Pecile A, Guidobono F, Netti C, Sibilia V, Biella G, Braga PC. Calcitonin gene-related peptide: antinociceptive activity in rats, comparison with calcitonin. Regul Pept 1987;18: 189-199.
17. Welch SP, Cooper CW, Dewey WL. An investigation of the antinociceptive activity of calcitonin gene-related peptide alone and in combination with morphine: correlation to 45Ca++ uptake by synaptosomes. J Pharmacol Exp Ther 1988; 244:28-33.
18. G Paxinos CW. The Rat Brain in Stereotaxic Coordinates. 6th, editor. Sydney: Academic Press; 2006.
19. Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 1977; 4:161-174.
20. Coderre TJ, Fundytus ME, McKenna JE, Dalal S, Melzack R. The formalin test: a validation of the weighted-scores method of behavioural pain rating. Pain 1993; 54:43-50.
21. Gebhart GF. Descending modulation of pain. Neurosci Biobehav Rev 2004; 27:729-737.
22. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest 2010; 120:3779-3787.
23. Garcia-Ramirez DL, Calvo JR, Hochman S, Quevedo JN. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord. PloS One 2014; 9:189-199.
24. Huang Y, Brodda-Jansen G, Lundeberg T, Yu LC. Anti-nociceptive effects of calcitonin gene-related peptide in nucleus raphe magnus of rats: an effect attenuated by naloxone. Brain Res 2000; 873:54-59.
25. Su HC, Wharton J, Polak JM, Mulderry PK, Ghatei MA, Gibson SJ, et al. Calcitonin gene-related peptide immunoreactivity in afferent neurons supplying the urinary tract: combined retrograde tracing and immunohistochemistry. J Neurosci Res 1986; 18:727-747.
26. Harmann PA, Chung K, Briner RP, Westlund KN, Carlton SM. Calcitonin gene-related peptide (CGRP) in the human spinal cord: a light and electron microscopic analysis. The J Comp Neurol 1988; 269:371-380.
27. Poyner DR. Calcitonin gene-related peptide: multiple actions, multiple receptors. Pharmacol Ther 1992; 56:23-51.
28. Dobolyi A, Irwin S, Makara G, Usdin TB, Palkovits M. Calcitonin gene-related peptide-containing pathways in the rat forebrain. J Comp Neurol 2005; 489:92-119.
29. Seybold VS. The role of peptides in central sensitization. Handb Exp Pharmacol 2009:451-491.
30. Sprenger T, Goadsby PJ. Migraine pathogenesis and state of pharmacological treatment options. BMC Med 2009; 7:65-76.
31. Khoshdel Z, Takhshid MA, Owji AA. Intrathecal Amylin and Salmon Calcitonin Affect Formalin Induced c-Fos Expression in the Spinal Cord of Rats. Iran J Med Sci 2014; 39:543-551.
32. Cridland RA, Henry JL. Effects of intrathecal administration of neuropeptides on a spinal nociceptive reflex in the rat: VIP, galanin, CGRP, TRH, somatostatin and angiotensin II. Neuropeptides 1988; 11:23-32.
33. Yu L-C, Weng X-H, Wang J-W, Lundeberg T. Involvement of calcitonin gene-related peptide and its receptor in anti-nociception in the periaqueductal grey of rats. Neurosci Lett 2003; 349:1-4.
34. Walker CS, Conner AC, Poyner DR, Hay DL. Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci 2010; 31:476-483.
Iranian Journal of Basic Medical Sciences
Volume 21, Issue 4
April 2018
Pages 395-399

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