Morphine Withdrawal Enhances Constitutive μ-Opioid Receptor Activity in the Ventral Tegmental Area

Abstract

-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.

Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence

“…Cessation of opiates leads to cellular and behavioral symptoms of withdrawal (12–16). An intriguing hypothesis of drug addiction suggests that chronic opiates increase MOR constitutive activity (MOR CA ) to preserve physical and psychological dependence (17–21), which is enhanced by enkephalins (22). Whether MORs adopt constitutive signaling states in other disease syndromes, such as chronic pain, is unknown.…”

Maturational alterations in constitutive activity of medial prefrontal cortex kappa‐opioid receptors in Wistar rats

“…As neutral antagonists for KORs are not well characterized, we tested the effect of CTOP (a neutral mu-opioid antagonist; Hawkins et al . 1989;Meye et al . 2012) on basal signaling.…”

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

“…An intriguing hypothesis of drug addiction suggests that chronic opiates increase MOR constitutive activity to preserve physical and psychological dependence (Wang et al, 1994, Liu and Prather, 2001, Wang et al, 2004, Shoblock and Maidment, 2006, Meye et al, 2012), which is enhanced by the action of endogenously released enkephalins in the brain (Shoblock and Maidment, 2007). Similarly, prolonged administration of exogenous opioid agonists, such as morphine or DAMGO, have been shown to cause an increase in the number of constitutively active opioid receptors during the period of opioid dependence (Wang et al, 2001a, Sadee et al, 2005, Walker and Sterious, 2005, Xu et al, 2007, Sally et al, 2010).…”

“…Constitutive activity is experimentally observable as increased basal GTPγS 35 binding, increased B max of the agonist-responsive high-affinity GTPγS 35 binding site and suppressed forskolin-stimulated cAMP accumulation. While constitutive activity is usually difficult to detect outside of in vitro heterologous cell expression systems, as described above (Costa and Herz, 1989, Liu and Prather, 2001, Wang et al, 2007), MOR CA has been observed in tissue obtained from the striatum (Wang et al, 2004, Shoblock and Maidment, 2006) and the ventral tegmental area (Meye et al, 2012) of morphine-dependent mice. Inverse agonists decreased basal GTPγS 35 binding, produced cAMP superactivation and disinhibited GABAergic signaling, indicative of acquired state-dependent activity following chronic receptor stimulation.…”