[D-Ala2]-methionine enkephalinamide reflexively induces antinociception by activating vagal afferents.

Experiment 1 showed that intravenous administration of [D-Ala2]-methionine enkephalinamide resulted in dose-dependent inhibition of the tail-flick reflex, mild hypotension, and bradycardia. The enkephalinamide-induced inhibition of the tail-flick reflex and cardiovascular effects were eliminated in the bilateral cervical vagotomized anesthetized rat preparation, but were unaffected by either a unilateral right vagotomy or bilateral sinoaortic deafferentation in the conscious rat preparation. Experiment 2 demonstrated that the antinociceptive and cardiovascular actions of enkephalinamide were eliminated by pretreatment with intravenous administration of the opioid-receptor antagonist naloxone. These experiments strongly suggest that peripherally circulating enkephalins could reflexively induce analgesia by activating cardiopulmonary receptors whose afferents travel in the vagi.