Hippocampal nicotinic acetylcholine receptor signaling mediates the anti-allodynic effect of ketamine and morphine on neuropathic pain.

The present study investigated the involvement of hippocampal nicotinic acetylcholine receptors (nAChRs) in the anti-allodynic effect of ketamine/morphine on neuropathic pain in adult male Wistar rats. Morphine or ketamine administration decreased the percentage of maximum possible effect (MPE%), indicating an analgesic effect. The most significant decrease occurred with a 5 mg/kg dose of morphine (average MPE% = 98), while a 0.5 mg/kg dose of ketamine resulted in a high response (average MPE% = 91), using decision trees as a machine learning tool. Combining morphine and ketamine improved neuropathic pain (average MPE% = 91). Intra-CA1 microinjection of mecamylamine (2 μg/rat) with morphine (3 mg/kg) reduced neuropathic pain (average MPE% = 94). Co-administration of lower doses of ketamine (0.1 mg/kg, i.p.) and mecamylamine (0.5 or 1 μg/rat) with morphine (3 mg/kg) led to a considerable reduction in pain (average MPE% = 91). Utilizing the generalized least squares (GLS) model enabled the establishment of a continuous relation between drug dose and MPE% as the outcome of interest. There was a 19.60 higher average MPE% for each mg/kg increase in morphine dose. In contrast, there was a 17.05 higher average MPE% for every 0.1 mg/kg increase in ketamine dose. Each 0.1 mg/kg increase in ketamine dose, when combined with morphine (3 mg/kg), led to a 30.85 higher average MPE%. A tenfold impact of increasing mecamylamine dosage on MPE% was observed when paired with morphine. Thus, hippocampal nAChRs play a significant role in mediating the anti-allodynic effect of ketamine and morphine in neuropathic pain.