Sleep-pain co-regulation by targeting the 5-HT2A receptor subtype: Mechanisms, promises and perils

Serotonin (5-HT) receptors, classified as 5-HT1-7, are known to mediate a constellation of physiological functions ranging from cognitive performance to regulation of sleep-wake cycle and pain perception. Although these functions have extensively been studied in association with various types of 5-HT receptors (5-HTRs), co-regulation of wakefulness and nociceptive processing by 5-HT2A subtype has remained largely unaddressed. This research gap is further supported by evidence proposing a bidirectional regulatory pathway between sleep quality and pain sensitivity. The present brief review aimed to first gather the existing evidence and then piece relevant findings together to picture how central 5-HT2A receptors may reciprocally regulate the sleep-pain physiological interplay. In depth review of literature indicates that sleep deprivation promotes the activation of these receptors which on one hand increases pain sensitivity and on the other hand reduces the REM sleep period, both of which further exacerbate the sleep quality through establishment of a vicious cycle. Collectively, pharmacological antagonism of 5-HT2A receptors has been found to relieve pain and improve sleep disturbances, however, these beneficial effects might be seriously challenged by respiratory and cognitive side effects. Precise pharmacological assessments are required to reveal the efficacy and address safety concerns in relation with this therapeutic approach.