Regulation and function of spinal and peripheral neuronal B 1 bradykinin receptors in inflammatory mechanical hyperalgesia

Activation of either B 1 or B 2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B 2 agonists activate sensory neurones directly, B 1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B 1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B 1 receptors in inflammatory hyperalgesia. Therefore we have examined B 1 bradykinin receptor regulation in rat dorsal root ganglia in a model of inflammatory hyperalgesia, and correlated it with hyperalgesic behaviour. Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B 1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B 1 protein in ipsilateral dorsal root ganglia. In behavioural experiments, the B 1 antagonist desArg 10 HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia. The B 1 agonist, desArg 9 BK, did not affect paw withdrawal thresholds in naı̈ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg 9 BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B 1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.