The Balance of MU-Opioid, Dopamine D2 and Adenosine A2A Heteroreceptor Complexes in the Ventral Striatal-Pallidal GABA Antireward Neurons May Have a Significant Role in Morphine and Cocaine Use Disorders

Abstract

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders. In cocaine use disorder it was found that irreversible A2AR-D2R complexes with an allosteric brake on D2R recognition and signaling are formed in increased densities in the ventral enkephalin positive striatal-pallidal GABA antireward neurons. In this perspective article we discuss and propose how an increase in opioid heteroreceptor complexes, containing MOR-DOR, MOR-MOR and MOR-D2R, and their balance with each other and A2AR-D2R complexes in the striatal-pallidal enkephalin positive GABA antireward neurons, may represent markers for development of morphine use disorders. We suggest that increased formation of MOR-DOR complexes takes place in the striatal-pallidal enkephalin positive GABA antireward neurons after chronic morphine treatment in part through recruitment of MOR from the MOR-D2R complexes due to the possibility that MOR upon morphine treatment can develop a higher affinity for DOR. As a result, increased numbers of D2R monomers/homomers in these neurons become free to interact with the A2A receptors found in high densities within such neurons. Increased numbers of A2AR-D2R heteroreceptor complexes are formed and contribute to enhanced firing of these antireward neurons due to loss of inhibitory D2R protomer signaling which finally leads to the development of morphine use disorder. Development of cocaine use disorder may instead be reduced through enkephalin induced activation of the MOR-DOR complex inhibiting the activity of the enkephalin positive GABA antireward neurons. Altogether, we propose that these altered complexes could be pharmacological targets to modulate the reward and the development of substance use disorders.

Keywords: G protein-coupled receptor; adenosine A2A receptor; cocaine use disorder; dopamine D2 receptor; morphine use disorder; mu opioid receptor; oligomerization, morphine.

FIGURE 1

A propose model on the existence of MOR, D2R and A2AR homo-and heteroreceptor complexes in balance with each other in the ventral striatal-pallidal GABA antireward neurons, shown as dimers. The MOR monomer and its intramolecular interactions are shown in the left panel. The orthosteric MOR receptor binding site is indicated in yellow to which e.g., the MOR agonist DAMGO (in green) can bind. The allosteric MOR binding site is shown in yellow. The intermolecular receptor-receptor interactions in adenosine, dopamine and opioid homo-and heteroreceptor complexes, shown as dimers, are indicated in the right panel. The balance between the oligomers is indicated by two arrows perpendicular to each other. It should be noted that A2R-dopamine D4 receptor (D4R) heteroreceptor complexes also exist in the rat forebrain, as demonstrated by the proximity ligation assay (Borroto-Escuela and Fuxe, 2019; Borroto-Escuela et al., 2020a). They were found in substantial densities in the prefrontal cortex, especially in the somatic membrane of the internal pyramidal cell layer V, and in the dorsal hippocampus, especially in the pyramidal cell layer (Borroto-Escuela and Fuxe, 2019). They also exist in high densities in the nucleus accumbens and dorsal striatum including both striosome and matrix compartments. Moreover, the D4Rs in the cortical regions have a role in cognition (Furth et al., 2013) that may be modulated by A2AR through the demonstrated A2AR-D4R heteroreceptor complexes in the prefrontal cortex and the hippocampus. Whether these receptor complexes have a role in cocaine and morphine use disorders, requires further analyses.

FIGURE 2

Understanding the role of the A2AR-D2R heteroreceptor complexes in modulating the changes in the activity of the ventral striatal-pallidal GABA antireward neurons induced by chronic morphine treatment or morphine self-administration. (A) Morphine (chronic) is shown to increase the density of D2R-D2R homomers (2 arrows pointing upwards). This causes enhanced inhibition of firing in the antireward neurons leading to a reduction of antireward activity. An increase of morphine self-administration is found. The D2R-MOR complex also becomes increased in density after morphine (chronic) mainly due to inhibition MOR internalization. This event will result in a reduction of MOR cycling, which impairs its signaling, and a reduction of recognition also develops due to antagonistic allosteric receptor-receptor interactions. As a result, an increase in morphine tolerance takes place since higher doses of morphine are needed to induce reward due to the malfunction of the MOR signaling. It is also proposed that an increased density of A2AR-D2R complexes develops upon exposure to chronic morphine as seen from the two red arrows indicated. As a result, the D2R function becomes reduced through an allosteric brake on D2R signaling. The MOR-DOR complex is well known to be increased in density upon chronic morphine treatment or morphine self-administration, shown by 2 arrows. Both receptor protomers remain functional by coupling to Gz protein. However, the morphine activation of the DOR protomer is known to produce a brake on MOR recognition via an allosteric receptor-receptor interaction. Therefore, an increase in morphine tolerance takes place. (B) Modulation of morphine effects by receptor protomer ligands. The D2R antagonist is known to block the inhibitory D2R homomer signaling over Gi/o and produces a marked reduction of morphine self-administration. In the case of the D2R-MOR complex, the D2R antagonist appears to disrupt the complex and set the MOR protomer free from D2R mediated allosteric inhibition. MOR internalization is therefore increased and its function restored, leading to a reduction of morphine tolerance due to enhanced MOR signaling induced by morphine. It is indicated that the A2AR agonist given in vivo should effectively inhibit the function of the D2R protomer of the A2AR-D2R complex, increased in density (see A). Thus, a reduction of the inhibitory Gi/o activity of the D2R protomer develops which results in an increase in the activity of the anti-reward GABA neurons. A reduction of morphine self-administration should develop. The DOR antagonist can target the DOR protomer and remove its allosteric inhibition of the MOR signaling, which reduces morphine tolerance.