Different neural systems mediate morphine reward and its spontaneous withdrawal aversion

The opponent‐process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non‐drug‐dependent rats were examined using a place‐conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non‐dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non‐dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself.