Brain kinin B1 receptor contributes to the onset of stereotypic nocifensive behavior in rat

Abstract

While brain kinin B1 receptor (B1R) is virtually absent in control rats, it contributes to hypertension via a midbrain dopaminergic (DA) mechanism in spontaneously hypertensive rat (SHR) and Angiotensin II (Ang II)-induced hypertension. This study aims at determining whether B1R can also affect stereotypic nocifensive behavior through DA and/or other neuromediators in the same models. The selective B1R agonist Sar[D-Phe8][des-Arg9]BK was injected i.c.v. (1μg/site) to freely behaving SHR (16 weeks), Ang II-hypertensive rats (200ng/kg/min×2 weeks, s.c.) and control Wistar-Kyoto rats (WKY). Behavioral activity to the agonist was measured before and after treatment with receptor antagonists (10μg/site i.c.v. or otherwise stated) for B1 (SSR240612), tachykinin NK1 (RP67580), glutamate NMDA (DL-AP5), DA D1 (SCH23390, 0.2mg/kg s.c.) and D2 (Raclopride, 0.16mg/kg s.c.). Other studies included inhibitors (10μg/site) of NOS (l-NNA) and iNOS (1400W). The possible desensitisation of B1R upon repeated intracerebral stimulation was also excluded. B1R expression was measured by qRT-PCR in selected areas and by immunohistochemistry in the ventral tegmental area. Results showed that the B1R agonist had no effect in WKY, yet it induced nocifensive behavioral manifestations in both models of hypertension (face washing, sniffing, head scratching, rearing, teeth chattering, grooming, digging, licking, wet-dog shakes). These responses were prevented by all antagonists and inhibitors tested, but 1400W had a less inhibitory effect on most behaviors. Compared with WKY, B1R mRNA levels were markedly enhanced in hypothalamus, ventral tegmental area and nucleus accumbens of SHR and Ang II-treated rats. B1R was detected on DA neuron of the ventral tegmental area in SHR. Data suggest that kinin B1R is upregulated in midbrain DA system in hypertensive rats and its i.c.v. activation induced stereotypic nocifensive behavior that is mediated by several mediators, notably substance P, glutamate, DA and NO.