| Kinins are important peptide mediators in inflammation and pain. They exert their effects by selective activation of two distinct G-protein coupled receptors termed B1 and B2. The present study was designed to evaluate the putative role of spinal B1 receptor on thermonociception in the STZ-diabetic rat (65mg/kg i.p.) using the tail-flick test. Various selective antagonists or agonists were administered intrathecally (i.t.) in Sprague Dawley (250–275 g) rats. The B1 receptor agonist, des-Arg9-BK (8.1 nmol) i.t. produced a biphasic response, a transient (1 min) hyperalgesia followed by a hypoalgesia (5–10 min) (24, 48, 72 h and 1, 2, 3 weeks after STZ). In control rats, this agonist did not modify the nociceptive threshold. The biphasic response was reversibly blocked by antagonists for B1 receptor, des-Arg10-Hoe 140 (8.1 nmol), or for GABAB receptor, CGP52432 (100 nmol). The hyperalgesic response to des-Arg9-BK was reversibly blocked by the prior i.t. injection of antagonist for tachykinin NK1 receptor (LY 306740, 6,5 nmol), by non selective COX-1 and -2 or selective COX-2 inhibitors (indomethacin, 10 μg or L 745337, 10 μg), by the nitric oxide (NO) synthase inhibitor (L-NNA, 10 μg) or by the antagonist for α2-adrenergic receptor (idazoxan, 10 μg). The biphasic response of des-Arg9-BK was not blocked by antagonists of NMDA receptor (APV, 2 nmol, i.t.), opioid receptors (naloxone, 10 μg, i.t.) or by tryptophan hydroxylase inhibitor (pCPA 300 and 100 mg i.p.). Insulin (2 UI/day s.c.) and the antioxidant tempol (30 mg/kg/day i.p.) blocked the hyperalgesic response to des-Arg9-BK (24 h and 1 and 2 weeks). The results suggest that the B1 receptor modulates the thermonociception in STZ-diabetic rats through the release of substance P, NO, noradrenaline, prostaglandins and GABA in the spinal cord. |
