Oral and spinal melatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors

Abstract

The antiallodynic effect of melatonin after intrathecal (it) and oral administration as well as the possible participation of MT(2) and opioid receptors in melatonin-induced antiallodynia in neuropathic rats were assessed. Ligation of the L5/L6 spinal nerves produced a clear-cut tactile allodynia in the rats. Intrathecal (3-100 microg) and oral (37.5-300 mg/kg) administration of melatonin decreased tactile allodynia induced by spinal nerve ligation. Intrathecal administration of the preferential MT(2) receptor antagonist luzindole (1-100 microg), but not vehicle, significantly diminished in a dose-dependent manner the antiallodynic effect induced by melatonin (100 microg, it). Oral (0.01-1mg/kg) or intrathecal (0.1-10 microg) administration of the highly selective MT(2) receptor antagonist 4P-PDOT diminished the antiallodynic activity induced by oral (150 mg/kg) or intrathecal (100 microg) administration of melatonin, respectively. Subcutaneous (1mg/kg) or intrathecal (0.5-50 microg) treatment with naltrexone, but not vehicle, significantly diminished the antiallodynic effect induced by oral (150 mg/kg) or intrathecal (100 microg) administration of melatonin. Oral melatonin (150 mg/kg)-induced antiallodynia was partially reduced by the spinal administration of 4P-PDOT (10 microg). Moreover, the spinal effect of melatonin (100 microg) was significantly reduced by the combination 4P-PDOT (0.1 microg)-naltrexone (0.5 microg). At the greatest tested doses, the antagonist drugs did not modify tactile allodynia in neuropathic rats. Melatonin (100 microg or 300 mg/kg) did not affect motor co-ordination in the rotarod test. Results indicate that melatonin reduces tactile allodynia in neuropathic rats after intrathecal and oral administration. Moreover, data suggest the participation of spinal MT(2) and opioid receptors in the melatonin-induced antiallodynic effect in this model.

Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dummy, controlled trial

“…This hypothesis is supported by the relation between BDNF and pro-inflammatory cytokines that has been demonstrated in FM patients [62-64]. Melatonin has marked anti-inflammatory effects on peripheral sites by inhibiting the release of pro-inflammatory cytokines [12]. Additional mechanisms involved in melatonin’s effect on pain pathways include an important reduction of nitric oxide (NO) and malondialdehyde (MDA) levels, two compounds that are closely related to inflammation [65].…”

“…Noradrenergic projections from the locus coeruleus produce similar effects [25]. Together, this evidence justifies assessing the effect of melatonin in the descending modulatory pain systems, alone or combined with classic therapeutic agents such as amitriptyline, as it has been demonstrated that melatonin increases the pain threshold in healthy subjects [26], improves sleep quality [15] and modulates systems involved in pain, such as the GABAergic and opioidergic systems [12,27,28]. …”

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

“…However, it is important to note that the effect of MLT was also blocked by the subcutaneous and intrathecal administration of naltrexone, thus indicating that opioids are also likely involved in the analgesic properties of MLT. 164 Arreola-Espino and colleagues 162 found that the oral administration of MLT dose-dependently reduced flinching behaviour in the 0.5% formalin test and tactile allodynia in diabetic rats. Remarkably, the MT 2 receptor antagonist K-185 blocked the effects due to MLT treatment.…”

“…160 Studies aimed at assessing the role of MLT receptors in the analgesic effect of MLT have shown that MT 2 and not MT 1 receptors are likely involved. [161][162][163][164] Yoon and colleagues 161 found that an intrathecal injection of MLT dose-dependently attenuated the flinching response during phases 1 and 2 of the formalin test in rats. The analgesic effect of MLT was blocked by the intrathecal administration of luzindole or 4P-PDOT, and consequently, it was mediated by the MT 2 receptor.…”

“…164 This effect was the result of the activation of spinal MT 2 receptors, since it was blocked by an intrathecal injection of luzindole or 4P-PDOT. However, it is important to note that the effect of MLT was also blocked by the subcutaneous and intrathecal administration of naltrexone, thus indicating that opioids are also likely involved in the analgesic properties of MLT.…”