Physical dependence produced by chronic intracerebroventricular infusion of [D-Arg]kyotorphin or thiorphan to rats.

Two compounds, [D-Arg]kyotorphin and thiorphan, unique in their mechanisms for producing an opioid-like analgesic response, were infused for six days into the lateral cerebral ventricle of rats. [D-Arg]kyotorphin (62.5 micrograms/microliter per h) and thiorphan (75 micrograms/5 microliter per h), but not vehicle infused animals, displayed certain behaviors characteristic of precipitated morphine withdrawal upon naloxone (10 mg/kg i.p.) challenge. Acute intracerebroventricular (i.c.v.) administration of [D-Arg]kyotorphin (62.5 micrograms/5 microliter) or thiorphan (75 micrograms/5 microliter) and subsequent challenge with naloxone resulted in no abnormal behavior. These data indicate that compounds which produce their analgesic effect through the modulation of endogenous opioids can cause physical dependence.