The N‐methyl‐D‐aspartate receptor antagonist ketamin exerts analgesic effects via modulation of the nitric oxide pathway

Abstract

Ketamine, an NMDA receptor antagonist, has been approved to have analgesic effects. It is known that nitric oxide pathway is involved in antinociception but with dual effects. In this study, we investigated the role of nitric oxide in ketamine‐induced analgesia. Ketamine was administered to mice acute and chronically with/without nitric oxide synthase (NOS) inhibitors. Experimental models of nociception pain, including hot plate, tail flick, and formalin tests, were performed. Western blot was used to measure levels of nitric oxide synthase enzymes in the brain. Ketamine doses of 0.03 and 0.3 mg/kg had significant analgesic effects (p < 0.01). High‐dose chronic ketamine could induce analgesia in later phases of the treatment in tail flick test (p < 0.01). Pretreatment with various NOS inhibitors decreased the analgesic effect. In western blot analysis, the expression of NOS proteins was decreased. Low‐dose ketamine is effective in analgesia induction. The expression of nNOS and iNOS proteins is dependent on the inhibition of the NMDA/NO pathway.

Ketamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression

“…Glutamate receptor ionotropic, NMDA 3A antagonist blocks the open ion channel directly and through negative allosteric regulation; prevents the activation of a calcium-dependent NO synthetase, which plays a role in nociception and neurotoxicity [59] 5-hydroxytryptamine receptor 3A potentiator increases voltage-gated potassium channel activity; binds at supratherapeutic doses, and is thought to increase the effects of the receptor through indirect mechanisms [60] α-7 nicotinic cholinergic receptor subunit antagonist its effects on skeletal muscle tone are not noticed unless unmasked by additional muscle relaxants; ketamine's NMDAR antagonism additionally inhibits acetylcholine release through the receptors [61] Muscarinic acetylcholine receptor M1 inhibitor primarily found in the hippocampus and the cerebral cortex [62] Nitric oxide synthase indirect inhibitor in the brain; functions through the glutamate/NO/cGMP system; may contribute to neuroprotective, sympathetic activating, and additional analgesic effects [63] Neurokinin 1 receptor antagonist through noncompetitive inhibition; possibly contributes to an analgesic effect, as this receptor modulates spinal cord nociception, but the therapeutic relevance of this interaction is not fully clear [64] Dopamine D2 receptor agonist/partial agonist specifically binds to the high-affinity state of the receptor; binding is more than 10 times weaker than that of dopamine and phencyclidine [65] Opioid receptors mild agonist binding affinity from strongest to weakest: mu > kappa > delta; related to some analgesic properties and adverse side effects, particularly with the kappa receptor [66,67] Sodium-dependent noradrenaline transporter inhibitor blocks reuptake in the heart, leading to increased chronotropy and vasoconstriction [68] Ketamine's mechanism of action as an anesthetic agent relies on its non-competitive antagonism of the NMDAR. These anesthetic effects, coupled with maintained blood pressure, spontaneous respiration, and laryngeal reflexes, made it a useful agent in various clinical scenarios [69].…”

Naphazoline and oxymetazoline are superior to epinephrine in enhancing the cutaneous analgesia of lidocaine in rats

“…Then, the curve was fitted by the computer-derived SAS NLIN Processes (SAS Institute Inc., Carey, NC) to derive the ED 50. [25,26] The ED 25 , ED 75 , and ED 95 were obtained by using the same method (SAS NLIN Processes) [27,28].…”