Administration of the Sleep‐Promoting Neuromodulator Adenosine Into the Median Preoptic and Septal Region Produced Thermal Hyperalgesia

Abundant clinical and preclinical evidence demonstrates that sleep and pain have bidirectional interactions. Sleep loss enhances pain perception and pain disrupts sleep. However, the exact neurobiological mechanisms through which sleep loss alters pain remain poorly understood. The preoptic area of the hypothalamus is crucial for the regulation of sleep onset and sleep homeostasis, and it innervates downstream regions that regulate arousal states and pain. Adenosine neurotransmission in the preoptic region plays a key role in the sleep homeostatic response following prolonged wakefulness or sleep deprivation. Previous studies showed that pharmacologically blocking adenosine A_2A receptors within the median preoptic nucleus of sleep-deprived rats prevented the increase in pain caused by sleep deprivation. These data suggest that preoptic adenosine levels, presumably elevated during sleep deprivation, increase pain sensitivity. Thus, here we investigated whether adenosine administration into the median preoptic nucleus of non-sleep-deprived, pain-naïve rats increased pain. Adenosine microinjection into the preoptic (and septal) regions significantly increased thermal hyperalgesia and extended the duration of pain-like behaviours after subcutaneous capsaicin injection, but did not affect mechanical hyperalgesia or the affective/motivational response in a mechanical conflict avoidance paradigm. Additionally, adenosine administration significantly reduced cFos expression in the ventrolateral periaqueductal grey, a key node in the descending pain modulation pathway. These data demonstrate that preoptic adenosine may act as a link between sleep disruption and pain.