CHRONIC INHIBITION OF ENKEPHALINASE INDUCES CHANGES IN THE ANTINOCICEPTIVE AND LOCOMOTOR EFFECTS OF THE ENKEPHALINASE INHIBITOR ACETORPHAN IN RATS

The enkephalinase inhibitor thiorphan was infused intracerebroventricularly in rats during 14 days (25-mu-g/5-mu-l/hr), inducing an average inhibition of cerebral enkephalinase of about 65%. Animals were tested during the infusion for their response to acetorphan, a parenterally active derivative of thiorphan. When administered intravenously on day 8 of the infusion, acetorphan (5 mg/kg) significantly increased locomotion in chronic saline-infused rats but not in animals receiving thiorphan. Furthermore, when injected at the same dose on day 10, acetorphan did not modify the latency to jump, in the hot plate test, in thiorphan-treated rats, whereas it elicited a significant analgesia in chronic saline-treated controls. These data show that the effects induced by the administration of an enkephalinase inhibitor were diminished after a period of chronic inhibition of the enzyme, suggesting the development of tolerance.