icatibant and Constriction--Pathologic

The present study was designed to examine the involvement of bradykinin in thermal and mechanical hyperalgesia induced by chronic constriction nerve injury (CCI) using B1 and B2 receptor antagonists and mutant kininogen-deficient rats.. Sprague-Dawley (SD) rats and Brown Norway (B/N-) rats given CCI treatment on day 0, were used as a model of neuropathic pain. Either a kinin B1 antagonist des-Arg9-[Leu8]-bradykinin or the receptor B2 antagonist HOE-140 was constantly infused into the left jugular vein of SD rats on days 15 to 22 after CCI. Vehicle-treated rats and sham-operated rats without nerve injury were also prepared as controls. In all rats, we observed pain behavior, and measured the latency period of paw withdrawal from the thermal stimuli and, with von Frey filaments, the mechanical pain threshold, before surgery and on days 14 and 22 after CCI. B/N-Katholiek rats, which congenitally lack plasma kininogen and release no kinin, were also tested for hyperalgesic parameters. Expression of kinin receptor mRNA in the dorsal root ganglia was detected by RT-PCR.. Most of the rats (88%) showed some pain behavior, which was reduced to 67% by a B1 antagonist and to 57% by a B2 antagonist infused between days 15 to 22. Thermal hyperalgesia was significantly reduced from 7.25 +/- 0.41 sec (mean +/- SEM) to 8.36 +/- 0.41 sec in paw withdrawal latency on day 22 by a B1 antagonist and from 7.24 +/- 0.19 sec to 8.23 +/- 0.21 sec by a B2 antagonist (P < 0.05). Mechanical hyperalgesia was also ameliorated from 0.02 +/- 0.007 g force to 0.16 +/- 0.08 g force in pain threshold by a B1 antagonist and from 0.03 +/- 0.007 g force to 0.10 +/- 0.003 g force on day 22 by a B2 antagonist. Moreover, deficient B/N-Katholiek rats showed a low incidence of thermal and mechanical hyperalgesia on day 14. Expression of both B1 and B2 receptor mRNAs was detected in the lumbar dorsal ganglia ipsilateral to the site of the nerve injury.. These data suggests that kinin were at least partly involved in yielding nociceptor hypersensitivity up to day 14 after CCI. Bradykinin and its B1 and B2 receptors were involved in the maintenance of hyperalgesia.

Topics: Animals; Behavior, Animal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Chronic Disease; Constriction, Pathologic; Ganglia, Spinal; Hot Temperature; Hyperalgesia; Kininogens; Male; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

We examined the role of B1 and B2 bradykinin receptors in promoting neuropathic hypersensitivity following peripheral nerve injury. Forty eight-hours following chronic constriction injury to a rat sciatic nerve there was an increased expression of B2 receptor mRNA in the lumbar dorsal root ganglia ipsilateral to the site of nerve injury. At 14 days following surgery there was also an ipsilateral increase of B1 receptor mRNA as well as a contralateral increased expression of B2 receptor mRNA. Increased expression of both receptors also coincided with analgesic effects of their antagonists. While HOE-140, a potent B2 receptor antagonist was analgesic at both time points tested, the B1 receptor antagonist des-Arg(9), [Leu(8)]-BK had an analgesic effect only at 14 days. The results support the concept that peripheral nerve injury is associated with local inflammation and that bradykinin, acting on both of its receptors promotes pain hypersensitivity.

Topics: Animals; Bradykinin; Constriction, Pathologic; Ganglia, Spinal; Hot Temperature; Lumbosacral Region; Male; Nervous System Diseases; Nociceptors; Pain; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; RNA, Messenger; Sciatic Nerve; Wounds and Injuries