ABSTRACT
This study used behavioural and in vivo electrophysiological paradigms to examine the effects of systemic and spinal administration of a bradykinin B1 receptor antagonist, compound X, on acute nociceptive responses in the rat. In behavioural experiments, compound X significantly increased the latency to withdraw the hindpaw from a radiant heat source after both intravenous and intrathecal administration, without affecting motor performance on the rotarod. In electrophysiological experiments, both intravenous and direct spinal administration of compound X attenuated the responses of single dorsal horn neurones to noxious thermal stimulation of the hindpaw. These data show that the antinociceptive effects of a bradykinin B1 receptor antagonist are mediated, at least in part, at the level of the spinal cord and suggest a role for spinal bradykinin B1 receptors in acute nociception.
Subject(s)
Amides/pharmacokinetics , Bradykinin B1 Receptor Antagonists , Naphthalenes/pharmacokinetics , Pain Measurement/methods , Pyrrolidines/pharmacokinetics , Spinal Cord/drug effects , Amides/administration & dosage , Animals , Carrageenan/administration & dosage , Carrageenan/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Electrophysiology/methods , Foot , Hindlimb , Hot Temperature/adverse effects , Hyperalgesia/etiology , Hyperalgesia/physiopathology , Hyperalgesia/prevention & control , Hypersensitivity/etiology , Hypersensitivity/physiopathology , Injections, Intravenous , Injections, Spinal , Male , Morphine/pharmacology , Naphthalenes/administration & dosage , Nociceptors/drug effects , Nociceptors/physiology , Psychomotor Performance/drug effects , Pyrrolidines/administration & dosage , Rats , Rats, Sprague-Dawley , Spinal Cord/physiologyABSTRACT
Intravenous administration of the NK1 receptor antagonist L-733,060 to gerbils 3 h before intraplantar injection of formalin caused a dose-dependent and complete inhibition of the late, but not early, phase nociceptive response (paw licking). The ID50 for L-733,060 (0.17 mg/kg) revealed a greater than 50-fold separation in potency over its less active enantiomer L-733,061 (ID50 > or = 10 mg/kg). In contrast, the non-brain penetrant quaternary ketone NK1 receptor antagonist, L-743,310 (3 mg/kg), did not attenuate the response to formalin, indicating that the antinociceptive effect of blockade of NK1 receptors by L-733,060 in this assay is centrally-mediated. These findings add to the preclinical evidence that NK1 receptor antagonists may be of therapeutic use as centrally-acting analgesics.
