title: Diabetic thermal hyperalgesia: role of TRPV1 and CB1 receptors of periaqueductal gray.
abstract: Hyperalgesia is one of the debilitating complications of diabetes. This condition might be caused by defects in central or peripheral processing of pain signals. In the present study we aim to see if diabetic hyperalgesia is related to changes in Transient Receptor Potential Vanilloid 1 (TRPV1) or Cannabinoid CB1 receptors of periaqueductal gray (PAG). Activation of glutamatergic projecting neurons in midbrain ventrolateral periaqueductal gray (VL-PAG) induces antinociception. Agonists of TRPV1 in VL-PAG increase firing of these glutamatergic neurons. CB1 receptor agonists also cause antinociception by decreasing Gamma Aminobutyric Acid (GABA) release in PAG and disinhibiting these glutamatergic neurons. In the present study antinociceptive effect of intra VL-PAG microinjections of CB1 and TRPV1 agonists [WIN55,212-2 (WIN) and capsaicin respectively] were compared in diabetic vs. non-diabetic rats, meanwhile mRNA expression of these receptors in PAG of diabetic and non-diabetic rats were evaluated by real time polymerase chain reaction (real time PCR) assay. Our results showed an attenuation of capsaicin antinociceptive effect (P<0.05) and TRPV1 receptor expression (P=0.023) but an increase in WIN antinociceptive effect (P<0.05) and CB1 receptor expression (P<0.001) in PAG of diabetic vs. non-diabetic rats. It is concluded that down-regulation of TRPV1 receptors in PAG is responsible for reduced antinociceptive effect of TRPV1 agonist. This finding may be an underlying cause of diabetic hyperalgesia. Up-regulation of CB1 receptors might be a compensatory mechanism but the precise elucidation of the effects of CB1 changes on disinhibition needs further studies.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Mohammadi-Farani
authors.forename: Mousa
authors.initials: M
authors.lastname: Sahebgharani
authors.forename: Zargham
authors.initials: Z
authors.lastname: Sepehrizadeh
authors.forename: Elham
authors.initials: E
authors.lastname: Jaberi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghazi-Khansari
mesh_terms: D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010487:Periaqueductal Gray / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002211:Capsaicin