Agomelatine potentiates anti-nociceptive effects of morphine in a mice model for diabetic neuropathy: involvement of NMDA receptor subtype NR1 within the raphe nucleus and periaqueductal grey
- 2 July 2020
- journal article
- research article
- Published by Informa UK Limited in Neurological Research
- Vol. 42 (7), 554-563
- https://doi.org/10.1080/01616412.2020.1757895
Abstract
Objectives: Opioid analgesics have been used for a long time in the treatment of acute and chronic pain. However, they have many side effects including tolerance development to a significant extent. Agomelatine, an atypical antidepressant, has been demonstrated to be effective in experimental studies on pain. However, the effect of agomelatine on morphine tolerance development and its mechanism of action are unknown. The antinociceptive effects of agomelatine, morphine and their combination were assessed in a mice model for painful diabetic neuropathy. The roles of glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit-1 (GluN1) in raphe nucleus and periaqueductal gray (PAG) in the effect of agomelatine on neuropathic pain were also investigated in diabetic mice. Methods: Agomelatine (10 mg/kg), morphine (10 mg/kg) and agomelatine + morphine were administered intraperitoneally for 15 consecutive days (twice per day), and the analgesic responses were assessed at days 1, 3, 6, 9, 12 and 15 in healthy and diabetic mice. Real time polymerase chain reaction (RT-PCR) was used to determine the changes in GluN1 expression. Results: The tolerance development for morphine was evident, started at 6th day and remained thereafter, but not for agomelatine. GluN1 in raphe nucleus and PAG was upregulated in morphine treated but not in agomelatine-treated groups. Discussion: The combination of agomelatine with morphine alone causes outlasting analgesic effects of repeated treatment, which can be interpreted as attenuated tolerance. Moreover, we also pointed out for the first time the modulatory effects of agomelatine on GluN1 expression in raphe nucleus and PAG after chronic morphine treatment.Keywords
Funding Information
- Turkish Scientific Technical Research Organization (115S290)
This publication has 32 references indexed in Scilit:
- Role of Melatonin in the Prevention of Morphine-Induced Hyperalgesia and Spinal Glial Activation in Rats: Protein Kinase C Pathway InvolvedInternational Journal of Neuroscience, 2011
- Tolerance to the Antinociceptive Effect of Morphine in the Absence of Short-Term Presynaptic Desensitization in Rat Periaqueductal Gray NeuronsThe Journal of pharmacology and experimental therapeutics, 2010
- Agomelatine, the first melatonergic antidepressant: discovery, characterization and developmentNature Reviews Drug Discovery, 2010
- Utility of saccadic eye movement analysis as an objective biomarker to detect the sedative interaction between opioids and sleep deprivation in opioid-naive and opioid-tolerant populationsJournal of Psychopharmacology, 2010
- Cingulate NMDA NR2B receptors contribute to morphine-induced analgesic toleranceMolecular Brain, 2008
- Amygdala GABA-A receptor involvement in mediating sensory-discriminative and affective-motivational pain responses in a rat model of peripheral nerve injuryPain, 2007
- Retinal Ganglion Cell Death in Glaucoma: Mechanisms and Neuroprotective StrategiesOphthalmology Clinics of North America, 2005
- Antiallodynic effects of intrathecally administered 5-HT2C receptor agonists in rats with nerve injuryPain, 2004
- Calcium‐Dependent Effects of Melatonin Inhibition of Glutamatergic Response in Rat StriatumJournal of Neuroendocrinology, 2001
- Inhibition by melatonin of dopamine release from rat hypothalamus: regulation of calcium entryBrain Research, 1983