Abstract
Abstract: The cholinergic system has been proposed to participate in the development of dependence on opioids. The present study examined effects of dermal pretreatment with methyl parathion (MP), an acetylcholinesterase inhibitor, on the development of physical dependence on morphine. Opioid dependence was induced by continuous intracerebroventri-cular (i.c.v.) infusion of morphine (26 nmol/µl/h) for 3 days in adult male Sprague-Dawley rats. Each rat received two doses of MP, 12.5 mg/kg, dermally, initially, 3 days prior to initiation of i.c.v. morphine infusion and again on the first day of infusion. Withdrawal was precipitated after 3 days of infusion by administering an opioid antagonist, naloxone (48 nmol/5 µl, i.c.v.). Twelve of 23 MP-treated rats exhibited signs of acetylcholinesterase inhibitor intoxication (mild tremors) and showed reduced spontaneous locomotor activity (tested by an open field test), prior to naloxone. The brain cholinesterase activity in these 12 rats was 13% of levels in control rats. Eleven rats that did not show toxic signs, exhibited cholinesterase activities that were 20% of control (not significant versus toxic group). The group that showed signs of MP intoxication exhibited a significantly lower incidence of opioid withdrawal jumping, rearing and wet dog shakes compared with the non-toxic group. No differences between quantal withdrawal signs (ptosis, penis-licking, and vocalization) were noted between the two groups. The results suggest that toxic inhibition of acetylcholin-esterase non-specifically reduces locomotor activity and may obscure certain behavioral signs of withdrawal from opioid dependence. This indicates that caution should be used in interpreting a direct involvement of acetylcholinesterase inhibition in preventing opioid dependence.
Highlights
Chronic treatment with opioid drugs, such as morphine, leads to development of physical dependence, which is characterized by a continuous need for drug in order to avoid physical discomfort
When examined 6 days after the first dose of methyl parathion (MP), 12 of the 23 showed signs of acetylcholinesterase inhibitor intoxication, i.e., slight tremor and lacrimation, while the remaining 11 rats showed no signs of toxicity
Brain cholinergic system has been proposed to be involved in opioid dependence and withdrawal, especially in the autonomic symptoms associated with opioid withdrawal [9]
Summary
Chronic treatment with opioid drugs, such as morphine, leads to development of physical dependence, which is characterized by a continuous need for drug in order to avoid physical discomfort (withdrawal symptoms). Anti-acetylcholinesterase agents elicit their effects through inhibition of acetylcholinesterase, thereby causing marked accumulation of acetylcholine in central and peripheral synapses and resulting in overstimulation of autonomic organs, skeletal muscle, and cholinergic receptors in the central nervous system [11]. Both acute and chronic treatments with an acetylcholinesterase inhibitor are known to result in depression of spontaneous locomotor activity and neuromuscular coordination [12]. This side effect of acetylcholinesterase inhibition may overshadow the expression of opioid withdrawal symptoms
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