Contributions of synaptic energetic dysfunction by microtubule dynamics and microtubule‐based mitochondrial transport disorder to morphine tolerance

Abstract Background and Purpose Morphine is among the most powerful analgesic, but its long‐term use can cause tolerance. Synaptic ATP supply is critical for maintaining synaptic transmission. Microtubule‐based mitochondrial transport ensures synaptic energy supply. How synaptic energy changes with morphine and the role of microtubule tracks in synaptic mitochondrial energy supply remain elusive. Chronic morphine treatment can destroy microtubule cytoskeletons. We investigated the effect of the microtubule cytoskeleton on synaptic mitochondrial energy supply and the mechanism of microtubule dynamics after morphine exposure. Experimental Approach Rats were treated with long‐term morphine and the effect on thermal pain thresholds was evaluated by the tail‐flick latency test. Various antagonists and agonists were used elucidated the role and mechanism of synaptic mitochondrial energy supply and microtubules in morphine tolerance in vivo and in SH‐SY5Y cells. Key Results Chronic morphine treatment reduced synaptic mitochondrial ATP production. Improving mitochondrial oxidative phosphorylation (OXPHOS) alleviated the downregulation of synaptic ATP levels. Microtubule‐stabilizing agents prevented microtubule disruption and ameliorated synaptic energy deficit via microtubule‐based microtubule transport. In SH‐SY5Y cells, morphine exposure reduced microtubule expression. And re‐opening the synaptic Ca 2+ channel by agonist alleviated microtubule decrease by calcium/calmodulin‐dependent protein kinase 2 (CAMKK2)/AMP‐activated protein kinase (AMPK) pathway. Conclusion and Implications This study demonstrates that the microtubule cytoskeleton regulated by the Ca 2+ –CAMKK2–AMPK axis is critical for synaptic mitochondrial transport and ATP production, explaining an interplay between chronic morphine‐induced abnormal neuroadaptation and synaptic energetic dysfunction. These findings implicated a potential clinical strategy for prolonging the opioid antinociceptive effect during long‐term pain control.