Beneficial effect of the opioid receptor antagonist naltrexone on hyper-sensitivity induced by spinal cord ischemia in rats: disassociation with MK-801

Abstract

In this study we examined the effect of the long-acting opioid antagonist naltrexone on the allodynia-like effect of spinal ischemia in rats. The spinal cord ischemia was induced at midthoracic level by a recently developed photochemical technique using laser irradiation and photoactivatable intravascular dyes. An allodynia-like sensory disturbance, where the animals reacted by vocalization to non-noxious mechanical stimuli in the flank area, was consistently seen during several days after ischemia. Pretreatment with 10 and 20 mg/kg, but not 5 mg/kg naltrexone i.v. 10 min before irradiation decreased the incidence of allodynia. However, even the effect of the highest dose of naltrexone (20 mg/kg) was incomplete, which is in contrast to the effect of the NMDA receptor antagonist MK-801, which has been tested in the same model and found to completely prevent the incidence of allodynia at a dose of 0.5 mg/kg. Pretreatment with sub- or suprathreshold doses of naltrexone (5 and 20 mg/kg respectively) combined with a subthreshold dose of MK-801 (0.1 mg/kg) did not produce a synergistic effect. When naltrexone (20 mg/kg) was administered 10 min after induction of ischemia, it was totally ineffective in decreasing the occurrence and severity of allodynia. In contrast, MK-801 (0.5 mg/kg) still had a good protective effect when injected as this time. Histological examination showed slight morphological damage in the spinal cord in 38% of control rats after 1 min laser irradiation without pretreatment with naltrexone. No morphological abnormalities were observed in rats after pretreatment with naltrexone (20 mg/kg). The results suggest that opioid receptor antagonists and NMDA receptor antagonists prevent a consequence of transient spinal cord ischemia through different mechanisms. High doses of opioid antagonists may have anti-ischemic effects by improving local spinal cord microcirculation and therefore may have a role in preventing ischemia after traumatic spinal cord injury. On the other hand, the NMDA receptor may have a role in the secondary neuronal death resulting from ischemia. Thus, NMDA receptor antagonists may contribute to the prevention of tissue damage by antagonizing the excitotoxic action of glutamate and/or aspartate released by ischemia into the spinal cord. Finally, since only high doses of naltrexone had an effect in the present study, we cannot rule out the possiblity that this drug may act through non-opioid mechanisms.