Role of alpha2-adrenoceptors in enhancement of antinociceptive effect in diabetic mice.
The present studies investigated behavioral and neurochemical aspects of the noradrenergic and serotonergic nervous systems in streptozotocin-induced diabetic mice. We previously reported that intrathecal (i.t.) injection of norepinephrine significantly potentiated antinociception in diabetic mice compared to that in non-diabetic mice, and that antinociception due to norepinephrine injection was completely abolished by pretreatment with yohimbine, an alpha2-adrenoceptor antagonist. The present studies demonstrated that i.t. injection of clonidine also showed more-potent antinociceptive activity in diabetic mice than in non-diabetic mice, but that i.t. methoxamine injection did not affect diabetic or non-diabetic mice. The antinociceptive potency due to i.t. injection of 5-HT was significantly lower in diabetic than in non-diabetic mice. In a neurochemical study, we found that the density of [3H]-rauwolscine binding sites in spinal alpha2-adrenoceptors was significantly higher in diabetic than in non-diabetic mice, but that the binding affinity was unchanged. Spinal norepinephrine turnover was determined by measuring the decline in tissue norepinephrine concentration at 3 h after injection of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine. The spinal norepinephrine concentration decreased to 43.7% from the baseline in non-diabetic mice, while it was 21.0% in diabetic mice. These results suggest that, based on the decrease of norepinephrine release in the spinal cord, up-regulation of spinal alpha2-adrenoceptors caused the increase of antinociception due to i.t. injection of an alpha2-adrenoceptor agonist in streptozotocin-induced diabetic mice, and it seemed that the stimulation of alpha2-adrenoceptors potentiated the antinociceptive effect. Thus, the spinal noradrenergic systems play an important moderating role in diabetes-induced neuropathic pain.
Omiya
Yuji
Y
Tsumura Research Laboratories, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki, 300-1192, Japan. oomiya_yuuji@mail.tsumura.co.jp
Yuzurihara
Mitsutoshi
M
Suzuki
Yasuyuki
Y
Kase
Yoshio
Y
Kono
Toru
T
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011312:Pressure; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D015016:Yohimbine; D019805:alpha-Methyltyrosine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D004791:Enzyme Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D013565:Sympatholytics; D015016:Yohimbine; D012701:Serotonin; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D008729:Methoxamine; D009638:Norepinephrine