Blockade of Serotonin 5-HT2A Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice.

Gang Pang,Xueke Liu,Yong-Mei Zhang,Robert W Stackman,Liuyi Dong,Ruoying Mao,Xinrong Tao,Xian Wu,Gongliang Zhang,Guangwu Li

doi:10.3389/fphar.2016.00514

Abstract

The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate – even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HT2AR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HT2ARs modulate opioid dependence and blockade of 5-HT2AR may represent a novel strategy for the treatment of morphine use disorders.Highlights(i)Blockade of 5-HT2A receptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5-HT2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.

Highlights

Morphine and other prescription opioids are the mainstay clinical treatment for moderate to severe acute pain
Our results indicated that blockade of 5-HT2A receptor (5-HT2AR) with MDL 11,939 suppressed morphine-induced hyperactivity, behavioral sensitization, and naloxone-precipitated withdrawal symptoms
Repeated morphine treatment was associated with an increase in 5-HT2AR expression and a decrease in extracellular signal-regulated kinases (ERK) phosphorylation in prefrontal cortex (PFC)

Summary

Introduction

Morphine and other prescription opioids are the mainstay clinical treatment for moderate to severe acute pain. The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths (Volkow et al, 2014). Morphine is a highly addictive opioid and the rate of relapse is remarkably high – even after long periods of abstinence (Blondell et al, 2013). The neural mechanisms underlying morphine addiction and relapse remain elusive (Volkow et al, 2014). 5-HT2A receptor (5-HT2AR) is a G protein-coupled receptor (GPCR) of the type A family. 5-HT2AR antagonist M100907 suppressed behavioral hyperactivity induced by cocaine (Fletcher et al, 2002), MK-801, amphetamine (O’Neill et al, 1999) and morphine (Auclair et al, 2004). There is little if any reports of the modulation of 5-HT2ARs on morphine-induced behavioral changes

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Results

Conclusion