Supraspinally administered agmatine prevents the development of supraspinal morphine analgesic tolerance

We have determined the effect of intracerebroventricularly (i.c.v.) administered decarboxylated arginine (agmatine) on supraspinally induced chronic morphine analgesic tolerance. Mice pre-treated with a schedule of chronic i.c.v administration of morphine (10 nmol, b.i.d. 3 days) show a 12-fold reduction in the potency of acutely administered i.c.v morphine compared to saline injected controls. Co-administration of agmatine (10 nmol) with one of the two daily morphine injections completely prevents the reduction in i.c.v morphine analgesia. Mice injected with agmatine once daily (but no morphine) do not show a increase in morphine analgesic potency relative to saline controls, indicating that a mere potentiation of acute morphine analgesia cannot account for the agmatine-mediated anti-tolerance effect in those mice subjected to the morphine tolerance induction schedule. These observations agree with previous reports that systemically and intrathecally administered agmatine prevent opioid tolerance, and extend these results to include a supraspinal site of action.