dextromethorphan and Spinal-Cord-Injuries

Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.

Topics: Animals; Behavior, Animal; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Gabapentin; Hyperalgesia; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord Injuries; Touch

This study examines the effects of agents purported to improve recovery following spinal cord trauma, methylprednisolone sodium succinate, dextromethorphan, and the combination of both, on the post-traumatic alterations of membrane lipid metabolism.. After sparing ten rats for a control group (G1) and performing T3-T6 laminectomies in 150 rats, spinal cord injuries were accomplished in 120 of 150 Wistar rats with an aneurysmal clip compression at the level of T4-5 for 30 sec. Hence the G2 group ( n 30) included the "only laminectomy/sham" group. The 120 injured animals were subdivided into four equal groups ( n 30 each). Group G3 underwent no therapy, G4 methylprednisolone (MP), G5 dextromethorphan (DM), and G6 MP+DM therapies. Groups G2-G6 were killed ten by ten at 10 min, 30 min, and 120 min after the operation. We measured tissue (MDA) and blood malonyldialdehyde (MDAb), (a product of lipid peroxidation) levels as an indicator of oxidative damage by thiobarbituric acid method and activity levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in erythrocytes. Intergroup and intragroup results were compared statistically.. Methylprednisolone was able to keep the levels for all parameters close to baseline except for 30-min MDA, MDA(b), and SOD values. But their results were all different from those of G3. Dextromethorphan was successful in this respect at 30-min GSH-Px and 120-min SOD and GSH-Px, and all values were also different from G3 values except for 10-min MDA, SOD, and GSH-Px. Combined therapy was not able to keep levels close to baseline for all parameters, but they were different from G3's except for the GSH-Px values. Methylprednisolone values displayed minimal alterations according to baseline at 120 min. Dextromethorphan was relatively unsuccessful at 10 min. Combined therapy did not show benefit superior to MP/DM single therapies.

Topics: Animals; Dextromethorphan; Drug Combinations; Erythrocytes; Excitatory Amino Acid Antagonists; Glutathione Peroxidase; Lipid Peroxides; Male; Malondialdehyde; Methylprednisolone; Neuroprotective Agents; Rats; Rats, Wistar; Spinal Cord Injuries; Superoxide Dismutase

A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemically administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury.

Topics: Animals; Behavior, Animal; Chronic Disease; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Ischemia; Motor Activity; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries

The potential role of excitatory amino acid (EAA) receptors in spinal cord trauma was examined in a standardized rat model of contusive injury. EAA antagonists were administered in a split-dose protocol with half given 5 min prior to and the remainder 15 min after contusion produced at the T8 vertebral level. Hindlimb function was assessed using a battery of tests of reflex and more complex behaviors at 1 day after injury and weekly thereafter through 4-8 weeks. Functional deficits were compared for groups administered intravenous MK 801 (1 mg/kg), dextromethorphan (10 mg/kg) and kynurenate (300 mg/kg) or the vehicle, saline, alone. In addition, possible effect of the drugs themselves on hindlimb function were assessed in uninjured controls. None of the drugs produced more than transient effect on uninjured rats. In contused rats, only kynurenate produced significant reductions in functional deficits as compared to saline controls. Significant improvement of hindlimb function was also observed when the thoracic cord was locally perfused with kynurenate via intrathecal cannulas and when kynurenate was directly infused into the contusive injury site by stereotaxic microinjection. Using the latter route of administration, a dose-dependent effect of kynurenate (100, 200 and 400 nmol) on the ability of contused rats to use their hindlimbs in locomotion was demonstrated. The highest dose also resulted in a significant reduction in overall functional deficits from 1 week through 1 month and at 2 months after injury. Our results support the hypothesis that EAA receptors at or near the injury site are involved in producing a proportion of the overall functional deficits stemming from traumatic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Analysis of Variance; Animals; Dextromethorphan; Dizocilpine Maleate; Female; Infusions, Intravenous; Injections, Spinal; Kynurenic Acid; Rats; Rats, Inbred Strains; Spinal Cord Injuries