α-Conotoxin TxIB Inhibits Development of Morphine-Induced Conditioned Place Preference in Mice via Blocking α6β2* Nicotinic Acetylcholine Receptors.

Xiaodan Li,Baojian Zhang,Sulan Luo,Dongting Zhangsun,Jian Xiong

doi:10.3389/fphar.2021.772990

Abstract

Morphine, the main component of opium, is a commonly used analgesic in clinical practice, but its abuse potential limits its clinical application. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry play an important role in the rewarding effects of abused drugs. Previous studies have showed that α6β2* (* designated other subunits) nAChRs are mainly distributed in dopaminergic neurons in the midbrain area, which regulates the release of dopamine. So α6β2* nAChRs are regarded as a new target to treat drug abuse. α-Conotoxin TxIB was discovered in our lab, which is the most selective ligand to inhibit α6β2* nAChRs only. Antagonists of α6β2* nAChRs decreased nicotine, cocaine, and ethanol rewarding effects previously. However, their role in morphine addiction has not been reported so far. Thus, it is worth evaluating the effect of α-conotoxin TxIB on the morphine-induced conditioned place preference (CPP) and its behavioral changes in mice. Our results showed that TxIB inhibited expression and acquisition of morphine-induced CPP and did not produce a rewarding effect by itself. Moreover, repeated injections of TxIB have no effect on learning, memory, locomotor activity, and anxiety-like behavior. Therefore, blocking α6/α3β2β3 nAChRs inhibits the development of morphine-induced CPP. α-Conotoxin TxIB may be a potentially useful compound to mitigate the acquisition and/or retention of drug-context associations.

Highlights

Morphine was usually used as a therapeutic drug for chronic pain and mental disorders caused by traumatic events (Holbrook et al, 2010)
On day 6, the escape latency was significantly decreased by training compared to day 2 (F4,192 24.83, p < 0.001), but there was no statistical difference among all groups α-Conotoxin TxIB Inhibits Morphine Addiction crossings (Figure 6B), latency of first time to target (Figure 6C), time and distance in target quadrant, percentage of time (Figure 6D), and distance (Figure 6F) in target quadrant were recorded and analyzed
The μ-opioid receptor is the key to the action of morphine and a series of studies show a strong relationship between the activation of the μ-opioid receptor located in the ventral tegmental area (VTA) and the reinforcing effects of morphine (Bodnar, 2016; Listos et al, 2019a)

Summary

Introduction

Morphine was usually used as a therapeutic drug for chronic pain and mental disorders caused by traumatic events (Holbrook et al, 2010). Compared with wild-type mice, nicotine induces CPP but at higher doses in α6 nAChR KO transgenic mice. These mice do not exhibit cocaine-induced CPP (Sanjakdar et al, 2015), but they express CPP following a lower dose of ethanol (Steffensen et al, 2018). The α6β2* nAChR antagonists, α-conotoxin MII [H9A; L15A] and r-bPiDI, decreased nicotine self-administration and CPP (Jackson et al, 2009; Beckmann et al, 2015). Despite many studies showing that α6β2* nAChR antagonists decrease nicotine, cocaine, and ethanol rewarding effects, their role in morphine addiction has not been reported so far

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