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 randomly 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 control groups (CON, n = 19). Physiologically controlled rats received fentanyl (fen) i.v., loading dose 800 micrograms kg-1 followed by maintenance dose 32 micrograms kg-1 min-1 for 2 h. Drug dosing: CON, isovolemic (between rats) 0.9% saline 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 mg kg-1 i.p. 18 h pre-fen. Seven days later all rats underwent cerebral perfusion fixation, followed by histologic grading (0-5, 0 = normal). Pathological data was analyzed by Wilcoxen's Signed rank test (two-tailed) for pathologic scores summated across all brain areas (overall severity score) and for scores of areas previously associated with opioid neurotoxicity. Compared 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 suggested 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 cortex 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 contribute to opioid neurotoxicity, and suggest a possible role of glutamate and histamine in opioid neurotoxicity.