Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-D-aspartate receptors

Abstract

BackgroundMorphine-induced hyperalgesia and tolerance significantly limits its clinical use in relieving acute and chronic pain. Melatonin, a pineal gland neurohormone, has been shown to participate in certain neuropsychopharmacological actions. The present study investigated the effect of melatonin on morphine-induced hyperalgesia and tolerance and possible involvement of protein kinase C (PKC)/N-methyl-D-aspartate (NMDA) pathway in melatonin-mediated.MethodsExperiments were performed on adult, male Sprague–Dawley rats. Melatonin (10 mg/kg, intraperitoneal, i.p.) or saline was administrated 10 min after morphine injection (10 mg/kg, subcutaneous, s.c.) each day for consecutive 14 days. Withdrawal threshold of the hindpaw to mechanical and thermal stimulation was measured before any drug administration and one hour after melatonin or saline on each designated test day. On the 15th day, thermal withdrawal was measured after s.c. morphine (20 mg/kg), but not melatonin, and morphine tolerance was measured and expressed by MPAE% (percent of maximal possible anti-nociceptive effect) of morphine. Levels of expression of protein kinase C gamma (PKCγ) and NMDA receptor subtype NR1 in spinal cord were detected by Western blotting.ResultsThe mechanical withdrawal threshold and thermal withdrawal latency decreased and shortened significantly (i.e., threshold decreased) in rats that received morphine treatment for two weeks compared with that in rats receiving saline. This morphine-induced mechanical and thermal hyperalgesia were greatly attenuated by co-administration of morphine with melatonin. The MPAE% representing morphine analgesic effect was reduced approximately 60% in rats that received morphine treatment. However, following the treatment of morphine with melatonin, the MPAE% was reduced only about 30%, comparing with those that received saline treatment as control. Administration of morphine alone resulted in significantly increased expression of PKCγ and NR1 proteins in the spinal cord. These increased levels of expression of PKCγ and NR1 were significantly inhibited by co-administration of morphine with melatonin.ConclusionsOur findings demonstrate that melatonin have potential to attenuate repetitive morphine-induced hyperalgesia and tolerance, possibly by inhibiting PKCγ and NR1 activities in the spinal cord.

N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia

“…The phosphorylation of MAPK family and the activation of glial cells in spinal dorsal horn induced by intraoperative remifentanil infusion can result in the production and release of multiple inflammatory mediators, and produce RIH [7, 36–38]. In addition to glia, the phosphorylation and activation of NMDAR in spinal neurons also resulted in the synaptic plasticity and enhanced sensory responses after intraoperative remifentanil infusion [4, 39–41]. The present study found that NAC can effectively decrease the phosphorylation of NR1, NR2B and MAPK family, decrease sensory neuron excitability and inhibit glial activation in spinal dorsal horn caused by remifentanil infusion.…”

α2δ-1–BoundN-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

“…5,7 Additionally, the glutamate N-methyl-d-aspartate (NMDA) receptors at the spinal cord level are critically involved in opioid-induced hyperalgesia and analgesic tolerance. 4,[8][9][10][11] Conventional NMDA receptors are located postsynaptically, but both acute and chronic opioid treatments predominantly affect presynaptic NMDA receptors in the spinal cord. 4,12,13 Chronic morphine administration diminishes postsynaptic NMDA receptor activity in the spinal dorsal horn.…”

<p>Role of Melatonin in the Regulation of Pain</p>

“…62 In morphine-exposed rodents, melatonin counteracted the resulting hyperalgesia and tolerance through inhibition of microglia activation and protein kinase Cγ (PKCγ) activities. [63][64][65] In the past 10 years, researchers have conducted an increasing number of studies on the antinociceptive effects of melatonin. In addition to animal experiments, clinical trials have been carried out in this field.…”

“…109,110 Conversely, melatonin is considered to exert protective effects by suppressing PKC. 63 The potential mechanisms remain controversial and require further investigation.…”