Effect of a Peripheral and a Central Acting Opioid Antagonist on the Testicular Response to Stress in Rats

The possible involvement of opioid receptors in mediating the inhibitory effects of immobilization stress on testicular steroidogenesis was determined in adult male rats. Unstressed controls and animals exposed to 3 h of immobilization stress were injected subcutaneously with either vehicle or 1 or 10 mg/ kg body weight (BW) of naloxone or naltrexone methobromide (NMB; an opioid receptor antagonist that does not cross the blood-brain barrier) at the beginning of and at 1.5 h of the stress period. Animals were sacrificed at 2 h (30 min after the second injection of antagonist) or 3 h (90 min after the second injection of antagonist) of stress. Plasma LH was not affected by stress, but 30 min after naloxone (1 or 10 mg/kg BW) injection, LH was elevated in both control and stressed rats above levels in vehicle-injected animals. By 90 min after naloxone injection, plasma LH had declined to levels comparable to those in vehicle-injected animals. NMB had no effect on plasma LH concentrations in either control or stressed rats. Three hours of stress reduced plasma testosterone (T) levels by 60% in vehicle-injected animals. This effect of stress on plasma T levels was antagonized by the 10 mg/kg BW dose of naloxone and 1 or 10 mg/kg BW of NMB. The ability of naloxone to reverse the effect of stress on plasma T levels was likely related to its ability to stimulate LH secretion, but NMB normalized plasma T values in stressed animals without altering plasma LH concentrations. Only the highest dose of NMB increased plasma T levels in unstressed control animals. The activities (Vmax) of testicular 17 α-hydroxylase and 17,20-lyase were significantly reduced by 3 h of stress. Km values for both enzymes were unchanged in stressed rats. Both naloxone and NMB normalized the activity of both enzymes in stressed animals, but did not alter the activity of the enzymes in unstressed rats. These results demonstrate that NMB, a peripheral acting opioid antagonist, counteracts the inhibitory effect of stress on plasma T levels and on testicular activity of 17 α-hydroxylase and 17,20-lyase independent of an effect on plasma LH concentrations. The study provides evidence for the involvement of peripheral opioid receptors (perhaps testicular opioid receptors) in mediating the inhibitory effect of immobilization stress on testicular steroidogenesis. Data from this study also supports the hypothesis that opioids directly modulate testicular testosterone secretion in unstressed control animals.