piperidines and Foot-Injuries

At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists.. Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days.. All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect.. The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

Topics: Acute Disease; Analgesics; Animals; Chronic Disease; Cold Temperature; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Foot Injuries; Hyperalgesia; Infrared Rays; Ketamine; Motor Activity; Neuralgia; Pain; Pain Measurement; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

Remifentanil is being used increasingly as one component of total intravenous anesthesia. Severe postoperative pain has occasionally been reported with discontinuation of remifentanil. This study was designed to determine the involvement of conventional protein kinase Cgamma (cPKCgamma) in the inhibitory action of lidocaine on remifentanil-induced hyperalgesia of rats after propofol-remifentanil-based anesthesia. Male Sprague-Dawley rats were allocated into the following groups randomly: propofol only (P), propofol+remifentanil (R), propofol+remifentanil+lidocaine (RL), and propofol+lidocaine (L). Cumulative pain score and withdrawal response to mechanical stimulation, immunoblotting, and immunofluorescence were applied to observe remifentanil-induced hyperalgesia and cPKCgamma membrane translocation. We found that the cumulative pain score of group R increased significantly at 30, 120, and 300 minutes postanesthesia (P<0.05). After plantar incision, the withdrawal threshold on both the contralateral and the ipsilaeral side at 30, 120, and 300 minutes postanesthesia in group R was significantly lower than in groups P, RL, and L (P<0.05). Both immunoblotting and immunofluorescence showed that cPKCgamma membrane translocation increased in dorsal horn neurons of propofol-remifentanil-based anesthetized rats, which could be inhibited by systemic lidocaine. These results suggested that increased cPKCgamma membrane translocation was involved in remifentanil-induced hyperalgesia, which was inhibited by systemic lidocaine and may contribute to reduced postoperative pain in rats after propofol-remifentanil-based anesthesia.

Topics: Analgesics, Opioid; Anesthesia; Anesthetics, Local; Animals; Behavior, Animal; Cell Membrane; Dose-Response Relationship, Drug; Fluorescent Antibody Technique; Foot Injuries; Hyperalgesia; Lidocaine; Male; Pain Measurement; Piperidines; Posterior Horn Cells; Protein Kinase C; Protein Transport; Rats; Rats, Sprague-Dawley; Remifentanil; Subcellular Fractions