Endorphin mechanisms are responsible for the beneficial effects of opioid antagonists on cerebral function during relative cerebral ischaemia in rats

The present study was conducted to examine the mechanisms behind the previously reported beneficial effects of high doses of naloxone on impaired cerebral function due to hypotensive haemorrhage in spontaneously hypertensive rats (SHR). The stereo-specificity of the effects of two opioid receptor antagonists, naloxone (Nal) and Win 44.441-3 (Win), was tested. The effects of thyrotropin releasing hormone (TRH) were also examined, because this peptide has been shown to have beneficial effects in neuronal ischaemia due to spinal injury. In addition, we were interested in seeing what effect the GABA antagonist, bicucculine (Bic), had on cerebral function during relative ischaemia, because Nal in high doses is suspected to antagonize GABA transmission. Mean arterial pressure (MAP), heart rate (HR) and somatosensory evoked potentials (SEP) were recorded in chloralose-anaesthetized SHR. The rats were bled and MAP was rapidly lowered to 50 mmHg. This resulted in transient bradycardia and attenuated SEP. When the first SEP component had decreased to 40–50% of control, the animals were retransfused to a MAP of 60–80 mmHg, to prevent further deterioration of SEP, and maintained at the new pressure level for the rest of the experiment. Fifteen to twenty minutes later, Nal, Win, TRH or Bic was injected i.v. Both (–)Nal (5 mg kg-1) and (–)Win (imgkg-1) improved SEP in a stereospecific manner. (+)Naloxone or (+)Win did not affect SEP significantly. Thyrotrophin releasing hormone (2 mg kg -1) caused further attenuation of a late SEP component. The effects of Bic (0.15-0.25 mg kg-1) varied between animals but, on average, no significant effects were observed. Thus, the results strongly indicate the involvement of endogenous opioids in the pathophysiology of cerebral ischaemia and indicate beneficial effects of opioid receptor antagonists on cerebral function in this model of relative cerebral ischaemia.