Beneficial effect of the nonselective opiate antagonist naloxone hydrochloride and the thyrotropin-releasing hormone (TRH) analog YM-14673 on long-term neurobehavioral outcome following experimental brain injury in the rat.

Abstract

Neurobehavioral dysfunction following traumatic brain injury results, in part, from delayed biochemical changes initiated by the traumatic insult. Endogenous opioid peptides have been implicated as one type of neurochemical factor involved in the delayed pathological sequelae of central nervous system (CNS) injury, including brain trauma. Both opiate antagonists and thyrotropin-releasing hormone (TRH) and its analogs, which antagonize the physiologic effects of endogenous opioids, have been shown to improve cardiovascular, cerebrovascular, metabolic, and neurologic status following both traumatic and ischemic CNS injury. The present study evaluated the ability of the opiate antagonist naloxone hydrochloride to improve posttraumatic neurologic motor function following experimental fluid-percussion brain injury in the rat, and compared the therapeutic effectiveness of naloxone to the long-acting, centrally active TRH analog YM-14673. Thirty minutes following fluid-percussion brain injury of moderate severity, animals received an intravenous bolus of either naloxone (2.0 mg/kg with constant infusion of 1.7 mg/kg/h, n = 8), YM-14673 (1.0 mg/kg, n = 8), or saline (n = 8). Although naloxone caused a modest and nonsignificant increase in mean arterial blood pressure (MAP); YM-14673 significantly increased MAP within 5 min of administration (p < 0.05), an effect that continued up to 4 h postinjury. Postinjury administration of both naloxone and YM-14673 caused a significant improvement in neurobehavioral outcome which persisted up to 4 weeks postinjury. These results suggest that endogenous opioid peptides may be involved in the pathologic response to traumatic CNS injury and that pharmacotherapies directed at antagonizing opioid peptides may enhance neurobehavioral recovery after brain injury.