Functional interaction between orexin-1 and CB1 receptors in the periaqueductal gray matter during antinociception induced by chemical stimulation of the lateral hypothalamus in rats.
Chemical stimulation of the lateral hypothalamus (LH) with carbachol induces antinociception which is antagonized by blockade of orexin receptors in some pain modulatory sites in the tail-flick test. In this study, we evaluated the role of orexin-1 and CB1 receptors in the periaqueductal gray matter (PAG), a critical pain modulatory site, in mediation of antinociceptive responses induced by LH stimulation in rats.



One hundred thirty-two adult male albino Wistar rats weighing 180-250 g were unilaterally implanted with two separate cannulae into the LH and ventrolateral PAG (vlPAG). Intra-vlPAG administration of SB334867, as a selective orexin-1 receptor antagonist (0.5, 1.5, 5, 15 and 50 nM), or AM251, as a selective CB1 receptor antagonist (1, 3, 10, 30 and 100 nM), was performed just 5 min before carbachol (125 nM) microinjection into the LH.



Our findings showed that SB334867 or AM251 administration dose dependently prevented the development of LH-induced antinociception in rats. Treatment with two antagonists at the same time could not intensify their effects in comparison with separate administration of antagonists.



It seems that antinociceptive effect of intra-LH administration of carbachol is mediated, at least partially, through the activation of orexin-1 and CB1 receptors in the vlPAG.



This work demonstrates a pain modulatory role of the orexinergic system via the PAG in hypothalamic-mediated analgesia suggesting that orexins can be advantageously targeted to achieve analgesia. WHAT DOES THIS STUDY ADD?: OX1 receptor antagonist (SB334867) administration into the ventrolateral periaqueductal gray matter (vlPAG) dose dependently blocked the carbachol-induced antinociception. CB1 receptor antagonist (AM251) microinjection in the vlPAG prevented carbachol-induced antinociception in a dose-dependent manner. Concurrent administration of SB334867 and AM251 into the vlPAG did not reinforce the antinociceptive responses.
Cellular and Molecular Research Center & Department of Physiology, Qazvin University of Medical Sciences, Qazvin, Iran.
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Esmaeili
Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Reisi
Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Ezzatpanah
Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Haghparast@yahoo.com, Haghparast@sbmu.sc.ir.
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Haghparast
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D002217:Carbachol; D004195:Disease Models, Animal; D007026:Hypothalamic Area, Lateral / Q000187:drug effects*; D008297:Male; D008845:Microinjections; D009287:Naphthyridines; D064446:Orexin Receptors / Q000187:drug effects / Q000502:physiology*; D000068797:Orexins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010146:Pain / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013268:Stimulation, Chemical; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D000068797:Orexins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D014508:Urea; D002217:Carbachol