Ventral pallidal injections of a mu antagonist block the development of behavioral sensitization to systemic morphine

Acute activation of opioid receptors in the ventral pallidum increases motor behaviors in rats. The present study was designed to investigate the possibility that the ventral pallidum influences motor responses induced by chronic opiate treatments and to examine the receptors that may be involved in such an effect. For five consecutive days, ambulations were quantified after rats received once-daily intraperitoneal (i.p.) injections of morphine (10 mg/kg) or saline following bilateral intra-ventral pallidal injections of either saline (0.5 microl/hemisphere), the mu antagonist CTOP (2. 1 microg/0.5microl/hemisphere), or the D1 antagonist SCH23390 (0.25 microg/0.5microl/hemisphere). Behavioral sensitization to an acute morphine challenge (10 mg/kg i.p.) was assessed 72 h after terminating the repeated treatment regimen. Rats who repeatedly received the intra-ventral pallidal saline + i.p. morphine exhibited increases in ambulations during the chronic treatment protocol and this effect was greatly enhanced (i.e., sensitized) following the post withdrawal acute morphine challenge. Rats repeatedly treated with intra-ventral pallidal CTOP + i.p. morphine did not display a motor response either during the chronic treatment regime or to the acute morphine challenge; an effect not seen when CTOP was injected into brain structures located dorsal to the ventral pallidum. The rats repeatedly treated with intra-ventral pallidal injections of SCH23390 + i.p. morphine demonstrated a motor response during the chronic protocol but the magnitude of this response was not significantly enhanced by the acute morphine challenge. These results demonstrate that: 1) mu opioid and D1-like dopamine receptors in the ventral pallidum influence the increase in locomotion that occurs during repeated morphine treatments; and 2) mu opioid (but not D1) receptors in the ventral pallidum are important in the postwithdrawal sensitized response to morphine. Such observations indicate that the ventral pallidum plays a critical role in morphine-induced behavioral sensitization.