Melatonin Attenuates Pain Hypersensitivity and Decreases Astrocyte-Mediated Spinal Neuroinflammation in a Rat Model of Oxaliplatin-Induced Pain

Abstract

Neuroinflammatory response in spinal dorsal horn has been demonstrated to be a critical factor in oxaliplatin-induced pain. Melatonin has been shown to have anti-inflammatory and anti-allodynia effects in both preclinical and clinical studies. In the present study, we investigated the role of systemic administration of melatonin on oxaliplatin-induced pain. Intraperitoneal (i.p.) injection with oxaliplatin induced significantly mechanical allodynia and thermal hyperalgesia. Melatonin (i.p.) significantly alleviated mechanical allodynia and thermal hyperalgesia in the oxaliplatin but not sham-treated rats. The attenuation of nociceptive response persisted at least to 3 days after melatonin injection, throughout the entire observing window. Immunohistochemistry showed that oxaliplatin induced a significant increase of glial fibrillary acidic protein (GFAP) immunodensities, which could be suppressed by melatonin. Western blotting showed that GFAP protein levels were significantly elevated in the oxaliplatin-vehicle group. Melatonin significantly decreased oxaliplatin-induced upregulation of GFAP expressions. Oxaliplatin injection also enhanced the messenger RNA (mRNA) expressions of cytokines including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and chemokines including monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1 (MIP-1α) in the spinal dorsal horn, which could be significantly repressed by melatonin. In vitro study showed that mRNA levels of TNF-α, IL-1β, MCP-1, and MIP-1α in primarily astrocytes were significantly increased after lipopolysaccharide (LPS, 1 μg/ml) stimulation. Melatonin (10 and 100 μM) greatly inhibited synthesis of these inflammatory mediators, in a dose-related manner. Conclusively, our data provide a novel implication of anti-nociceptive mechanism of melatonin in chemotherapy-related pain.

Melatonin and Comorbidities in Children with Autism Spectrum Disorder

“…Recent animal studies on neuropathic pain, fibromyalgia, orofacial pain, and allodynia (painful sensation caused by an innocuous stimulus) have also documented the analgesic effects of melatonin. [ 69 – 74 ] Such studies indicate that melatonin could reduce inflammatory and oxidative stress by modulating the nitroxidergic system. Lin et al (2017) have identified MT2 melatonin receptors in the dorsal root ganglia as being involved in the melatonin analgesic effect on neuropathic pain.…”

Effects of Sleep Quality on Melatonin Levels and Inflammatory Response after Major Abdominal Surgery in an Intensive Care Unit

“…Moreover, Veneroso et al reported that melatonin reduced cardiac inflammatory injury induced by acute exercise by decreasing the mRNA levels of IL-1, IL-6 and TNF-α [ 7 ]. Similar effects of melatonin on interleukin levels in models of heat stroke, acute liver injuries, and neuroinflammation induced by methamphetamine- and oxaliplatin-induced pain, have been observed [ 8 , 9 , 10 , 15 , 16 ]. The other sites in which anti-inflammatory properties of melatonin were observed include renal, pancreatic, and even retinal tissue [ 17 , 18 , 19 ].…”

An Updated Understanding of the Mechanisms Involved in cHemotherapy-Induced Neuropathy

“…Paclitaxel leads to increased expression of this chemokine and its receptor, CCR2, in DRG in a paclitaxel model of CIPN [99], and neutralizing MCP-1/CCL-2 in DRG blocked macrophage infiltration and subsequent hyperalgesia in a paclitaxel rodent model of CIPN [128]. Oxaliplatin is also capable of increasing MCP-1/CCL-2, primarily released from astrocytes, at the time that hyperalgesia is occurring in rats; a finding that was decreased by treatment with melatonin [129]. Melatonin may further protect against oxaliplatin-induced CIPN by preventing mitochondrial dysfunction and eventual neuronal apoptosis, as was evidenced in a recent extensive study using a combination of in vitro and in vivo methods in human tissue and behavioral assessments in rats exposed to paclitaxel [130].…”