ANTINOCICEPTIVE PROFILE OF BIPHALIN, A DIMERIC ENKEPHALIN ANALOG

The dimeric enkephalin biphalin (Tyr-D-Ala-Gly-Phe-NH)2 was evaluated in mice using antinociceptive, gastrointestinal and physical dependenc e paradigms and compared with that of morphine (reference mu agonist) and etorphine (ultrapotent opioid agonist). Intracerebroventricular bi phalin was 6.7- and 257-fold more potent than etorphine or morphine in eliciting antinociception. When administered i.t., biphalin produced only a 60% maximal antinociceptive effect in the tail-flick test even when given at doses up to 3 orders of magnitude higher than those effe ctive i.c.v.; morphine was equipotent in this assay when given i.c.v. or i.t. Both morphine and biphalin were equipotent after i.p. administ ration. In spite of its antinociceptive effectiveness after i.p. admin istration, only a small fraction of [I-125]biphalin was shown to penet rate to the brain (0.051 +/- 0.011%, at 20 min). After i.c.v. administ ration, biphalin antinociception was antagonized by receptor selective doses of beta-funaltrexamine (mu antagonist), naloxonazine (mu1 antag onist), ICI 174,864 (delta antagonist) and [D-Ala2,Cys4]deltorphin (de lta2 antagonist), but not by [D-Ala2,Leu5,Cys6]enkephalin (delta1 anta gonist) or nor-binaltorphimine (kappa antagonist), whereas etorphine a ntinociception was significantly antagonized only by beta-funaltrexami ne and naloxonazine Intracerebroventricular biphalin inhibited gastroi ntestinal propulsion at doses 8-fold higher than those producing i.c.v . antinociception; i.c.v. morphine showed a similar antinociceptive an d gastrointestinal propulsion A50. Intraperitoneal biphalin, but not i .p. morphine, showed little, if any, physical dependence, but both bip halin and morphine produced significant physical dependence when equia ntinociceptive doses were infused i.c.v. These results demonstrate an unusual profile for biphalin which suggests a potentially novel mechan ism which may involve, in part, the putative opioid receptor complex o f physically or functionally interacting mu and delta2 opioid receptor s. Biphalin may thus represent the first in a series of such compounds which may lead to significant therapeutic advantages.