Melatonin Moderates the Triangle of Chronic Pain, Sleep Architecture and Immunometabolic Traffic

Abstract

Preclinical as well as human studies indicate that melatonin is essential for a physiological sleep state, promotes analgesia and is involved in immunometabolic signaling by regulating neuroinflammatory pathways. Experimental and clinical neuromodulation studies for chronic pain treatment suggest that neurostimulation therapies such as spinal cord stimulation, vagus nerve stimulation and dorsal root ganglion stimulation have an impact on circulating inflammatory mediators in blood, cerebrospinal fluid and saliva. Herein, we provide an overview of current literature relevant for the shared pathways of sleep, pain and immunometabolism and elaborate the impact of melatonin on the crossroad of sleep, chronic pain and immunometabolism. Furthermore, we discuss the potential of melatonin as an adjunct to neurostimulation therapies. In this narrative review, we addressed these questions using the following search terms: melatonin, sleep, immunometabolism, obesity, chronic pain, neuromodulation, neurostimulation, neuroinflammation, molecular inflammatory phenotyping. So far, the majority of the published literature is derived from experimental studies and studies specifically assessing these relationships in context to neurostimulation are sparse. Thus, the adjunct potential of melatonin in clinical neurostimulation has not been evaluated under the umbrella of randomized-controlled trials and deserves increased attention as melatonin interacts and shares pathways relevant for noninvasive and invasive neurostimulation therapies.

Impact of Melatonin as a Premedication Agent in Caesarean Section on Blood Loss and Postoperative Pain Level

“…Melatonin has been observed to exhibit analgesic properties in both preclinical and clinical investigations [ 27 ]. The modulation of pain perception and the alleviation of pain can be achieved through interactions with particular receptors and neurotransmitters that are involved in pain signaling pathways [ 28 ]. Melatonin demonstrates anti-inflammatory properties by suppressing the secretion of proinflammatory cytokines and diminishing oxidative stress.…”

Efficacy and Safety of Preoperative Melatonin for Women Undergoing Cesarean Section: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

“…First, melatonin has been found to possess anti-inflammatory properties by suppressing the generation of pro-inflammatory cytokines and reducing the activity of inflammatory cells [ 41 , 42 ]. Second, melatonin modulates the perception of pain by interacting with the opioid system of the brain [ 43 , 44 , 45 ]. Opioids are a natural compound in the brain’s “endogenous opioids” and a type of medication commonly used to relieve pain.…”

“…They function by attaching to certain brain receptors [ 46 ]. It has been demonstrated that melatonin increases the activity of these opioid receptors, thus reducing pain [ 43 , 47 , 48 , 49 ]. Third, melatonin modulates the activity of other neurotransmitters involved in pain perception, including serotonin and dopamine [ 43 , 45 , 50 ], in addition to its antioxidant and opioid-related activities, which can help relieve pain and induce relaxation.…”

“…It has been demonstrated that melatonin increases the activity of these opioid receptors, thus reducing pain [ 43 , 47 , 48 , 49 ]. Third, melatonin modulates the activity of other neurotransmitters involved in pain perception, including serotonin and dopamine [ 43 , 45 , 50 ], in addition to its antioxidant and opioid-related activities, which can help relieve pain and induce relaxation. Fourth, melatonin is popularly known as a sleep aid, and research indicates that it can increase the quality and length of sleep [ 19 , 21 , 25 , 26 ].…”

Sleep disorders in chronic pain and its neurochemical mechanisms: a narrative review

“…Melatonin is a neuroendocrine hormone, mainly synthesized and secreted by the pineal gland, which has a wide range of physiological functions, including regulation of circadian rhythms, enhancement of immune function, improvement of sleep, and pain ( 107 ). Sleep deprivation enhances microglial activation and aggravates neuropathic pain by suppressing melatonin secretion in a CCI rat model ( 108 ).…”