Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems

Abstract

OBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that Nmethyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine is a non-competitive NMDA receptor antagonist drug and has well-known antinociceptive properties. The drug acts not only on NMDA receptors but also has effects on the monoaminergic system and non-NMDA glutamatergic receptors which have vital roles in the regulation of pain. This study was conducted to investigate the serotonergic and glutamatergic involvement in low-dose ketamine (20 mg/ kg) analgesia in mice. METHOD: The effects of serotonin were suppressed with two different ways; either the serotonin was depleted with p-chlorophenylalanine (pCPA, 150 mg/kg/d; 4 days) or the serotonin receptors were blocked with methiothepin (0.1 mg/kg), and α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) receptors were antagonized with GYKI-52466 (20 mg/kg). Fluoxetine (20 mg/kg; 7 days) was used to increase the serotoninergic activity. We used a hotplate (HP) test to measure pain reaction latencies. Furthermore, we tested sustained analgesic effects of ketamine for six consecutive times (1-hour break between each test). RESULTS: In our experiment, ketamine treatment increased pain reaction latencies, yet it failed to increase the latencies when combined with antiserotonergic drugs, e.g. pCPA and methiothepin. The latencies were increased with AMPA receptor blockade, yet ketamine did not increase the analgesic effect of the AMPA receptor antagonist, i.e. GYKI-52466. In consecutive tests, ketamine was effective for 5 h, and the peak effect was seen at the 3rd-hour test. CONCLUSION: Our data suggest that the activity of the serotonergic system and AMPA receptors are necessary for ketamine to produce antinociceptive effects. In pain management, ketamine can offer an alternative option to traditional analgesics and may be useful to reduce opioid tolerance.

Beyond the Raskin Protocol: Ketamine, Lidocaine, and Other Therapies for Refractory Chronic Migraine

“…Ketamine may also exert anti-nociceptive activity through direct activity on μ- and δ-opioid receptors and by induction of endogenous opioid synthesis [ 61 ]. Finally, in addition to NMDA receptor activity, ketamine’s anti-nociceptive effect is associated with increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPAR) activity and enhanced serotonergic neurotransmission [ 62 ].…”

The Efficacy of N-Acetyl-Cysteine (NAC) Supplementation in FST Model for Screening Antidepressants

“…N-acetylcysteine (NAC) (Swanson, 60-mg capsule) was purchased from H-Medix Abuja, Nigeria. NAC was given orally 60 min before the FST procedure according to Erdinc et al, (2019) and Magalhães et al, (2019) methods. One hour later they were subjected to FST for 5 min and the immobility time was recorded.…”

Cardamonin Modulates Neuropathic Pain through the Possible Involvement of Serotonergic 5-HT1A Receptor Pathway in CCI-Induced Neuropathic Pain Mice Model

“…The antagonists were administered intraperitoneally 30 min prior to cardamonin administration. All of the doses were determined based on previous literatures [ 58 , 59 , 110 , 111 ].…”