Opioid neurotoxicity: Role of neurotransmitter systems

We hypothesized that blockade of synthesis or release of several categories of neurotransmitters would ameliorate opioid neurotoxicity. Rats were rand omly assigned to one of six groups in two sequential protocols: vesamicol ( VES, n = 10), alpha -fluoromethylhistidine (FMH, n = 10), reserpine (RES, n = 10) BW1003C87 (BW, n = 7) lamotrigine (LAM, n = 10) or one of two contro l groups (CON, n = 19). Physiologically controlled rats received fentanyl ( fen) i.v., loading dose 800 mug kg(-1) followed by maintenance dose 32 mug kg(-1) min(-1) for 2 h. Drug dosing: CON, isovolemic (between rats) 0.9% sa line i.v.; BW, 20 mg kg(-1) i.v. 15 min pre-fen; LAM, 16 mg kg(-1) i.v. 30 min pre-fen; VES, 2.5 mg kg(-1) i.p. 60 min and 30 min pre-fen then infused 3.75 mg kg(-1) during fen; FMH, 20 mg kg(-1) i.p. 2 h pre-fen; RES, 0.75 m g kg(-1) i.p. 18 h pre-fen. Seven days later all rats underwent cerebral pe rfusion fixation, followed by histologic grading (0-5, 0 = normal). Patholo gical data was analyzed by Wilcoxen's Signed rank test (two-tailed) for pat hologic scores summated across all brain areas (overall severity score) and for scores of areas previously associated with opioid neurotoxicity. Compa red to CON, overall severity was decreased by RES (p = 0.05) with an effect suggested by VES (p = 0.10). Compared to CON, lesions were decreased: (a) in the amygdala with VES (p = 0.03) and RES (p = 0.05) with a trend suggest ed by BW (p = 0.06); (b) in the subiculum by VES (p = 0.02) and RES (p = 0. 008) with a trend suggested by FMH (p = 0.06); and (c) in the entorhinal co rtex by VES (p = 0.004) and RES (p = 0.008) with a trend suggested by FMH ( p = 0.07). The data indicate that brain acetylcholine and catecholamines co ntribute to opioid neurotoxicity, and suggest a possible role of glutamate and histamine in opioid neurotoxicity.