Blockade of Serotonin 5-HT(2A) Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice

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-HT(2A) receptors (5-HT(2A)Rs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT(2A)R 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-HT(2A)R 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-HT(2A)Rs modulate opioid dependence and blockade of 5-HT(2A)R may represent a novel strategy for the treatment of morphine use disorders. HIGHLIGHTS: (i).. Blockade of 5-HT(2A) receptors suppresses the expression of morphine-induced behavioral sensitization. (ii).. Blockade of 5-HT(2A) receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice. (iii).. Chronic morphine exposure induces an increase in 5-HT(2A) receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.