dynorphins and icatibant

Infraorbital nerve constriction (CION) causes hypersensitivity to facial mechanical, heat and cold stimulation in rats and mice and is a reliable model to study trigeminal neuropathic pain. In this model there is evidence that mechanisms operated by kinin B1 and B2 receptors contribute to heat hyperalgesia in both rats and mice. Herein we further explored this issue and assessed the role of kinin receptors in mechanical hyperalgesia after CION. Swiss and C57Bl/6 mice that underwent CION or sham surgery or dynorphin A (1-17) administration were repeatedly submitted to application of either heat stimuli to the snout or mechanical stimuli to the forehead. Treatment of the animals on the fifth day after CION surgery with DALBK (B1 receptor antagonist) or HOE-140 (B2 receptor antagonist), both at 0.01-1μmol/kg (i.p.), effectively reduced CION-induced mechanical hyperalgesia. Knockout mice for kinin B1, B2 or B1/B2 receptors did not develop heat or mechanical hyperalgesia in response to CION. Subarachnoid dynorphin A (1-17) delivery (15nmol/5μL) also resulted in orofacial heat hyperalgesia, which was attenuated by post-treatment with DALBK (1 and 3μmol/kg, i.p.), but was not affected by HOE-140. Additionally, treatment with an anti-dynorphin A antiserum (200μg/5μL, s.a.) reduced CION-induced heat hyperalgesia for up to 2h. These results suggest that both kinin B1 and B2 receptors are relevant in orofacial sensory nociceptive changes induced by CION. Furthermore, they also indicate that dynorphin A could stimulate kinin receptors and this effect seems to contribute to the maintenance of trigeminal neuropathic pain.

Topics: Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Dynorphins; Facial Pain; Hot Temperature; Hyperalgesia; Male; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Neurotransmitter Agents; Pain Measurement; Receptors, Bradykinin; Touch

The role of bradykinin (BK) receptors in activating and sensitizing peripheral nociceptors is well known. Recently, we showed that spinal dynorphin was pronociceptive through direct or indirect BK receptor activation. Here, we explored the potential role of BK receptors in pain associated with persistent pancreatitis in rats.. Experimental pancreatitis and abdominal hypersensitivity were induced by intravenous administrations of dibutyltin dichloride (DBTC). [des-Arg-Leu]BK (B1 antagonist) and HOE 140 (B2 antagonist) were given by intraperitoneal or intrathecal injection. Dynorphin antiserum was given intrathecally. Reverse transcription-polymerase chain reaction was used to detect spinal mRNA for BK receptors.. Dibutyltin dichloride-induced pancreatitis upregulated B1 and B2 mRNA in the thoracic dorsal root ganglion and B2, but not B1, in the pancreas. No changes in spinal B1 or B2 mRNA were observed. Intraperitoneal or intrathecal administration of HOE 140 dose dependently abolished DBTC-induced abdominal hypersensitivity, whereas [des-Arg-Leu]BK was without effect by either route of administration. Antiserum to dynorphin (intrathecal) abolished DBTC-induced hypersensitivity.. These results suggest that blockade of peripheral or spinal BK B2 receptors may be an effective approach for diminishing pain associated with pancreatitis. Moreover, it is suggested that spinal dynorphin may maintain pancreatitis pain through direct or indirect activation of BK B2 receptors in the spinal cord.

Topics: Abdominal Pain; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Dynorphins; Ganglia, Spinal; Gene Expression; Immune Sera; Injections, Intraperitoneal; Injections, Intravenous; Injections, Spinal; Male; Organotin Compounds; Pain; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord