Neurological correlates of brain reward circuitry linked to opioid use disorder (OUD): Do homo sapiens acquire or have a reward deficiency syndrome?

Abstract

The extant literature confirms that an array of polymorphic genes related to- neurotransmitters and second messengers govern the net release of dopamine in the Nucleus Accumbens (NAc) in the mesolimbic region of the brain. They are linked predominantly to motivation, anti-stress, incentive salience (wanting), and wellbeing. Notably, in 2000 the Nobel Prize was awarded to Carlsson, Greengard, and Kandel for their work on the molecular and cellular function of dopaminergic activity at neurons. This historical psychopharmacological work involved neurotransmission of serotonin, endorphins, glutamate, and dopamine, and the seminal work of Blum, Gold, Volkow, Nestler, and others related to neurotransmitter function and related behaviors. Currently, Americans are facing their second and worst opioid epidemic, prescribed opioids, and easy access drive this epidemic of overdoses, and opioid use disorders (OUDs). Presently the clinical consensus is to treat OUD, as if it were an opioid deficiency syndrome, with long-term to life-long opioid substitution therapy. Opioid agonist administration is seen as necessary to replace missing opioids, treat OUD, and prevent overdoses, like insulin is used to treat diabetes. Treatment of OUD and addiction, in general, is similar to the endocrinopathy conceptualization in that it views opioid agonist MATs as an essential core to therapy. Is this approach logical? Other than as harm reduction, is using opioids to treat OUD therapeutic or harmful in the long term? This historical Trieste provides a molecular framework to understand the current underpinnings of endorphinergic/dopaminergic mechanisms related to opioid deficiency syndrome and generalized reward processing depletion. WC 249.

Keywords: Brain reward Cascade (BRC); Dopamine deficiency syndrome; Dopamine release and homeostasis; Endorphinergic deficiency syndrome; Endorphinergic mechanisms; Genetic testing of addiction liability; Neurotransmission; Opioid use disorder (OUD); Precision addiction management’; Reward deficiency syndrome (RDS).

Fig. 1

The brain reward cascade. Fig. 1 illustrates the interaction of at least seven major neurotransmitter-pathways involved in the Brain Reward Cascade (BRC). In the hypothalamus environmental stimulation results in the release of serotonin, which in turn via, for example, 5HT-2a receptors activate (green equal sign) the subsequent release of opioid peptides from opioid peptide neurons, also in the hypothalamus. Then, in turn, the opioid peptides have two distinct effects, possibly via two different opioid receptors. One that inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin) and projects to the Substania Nigra to GABAA neurons. Another stimulates (green equal sign) cannabinoid neurons (the Anandamide and 2-archydonoglcerol, for example) through Beta –Endorphin linked delta receptors, which in turn inhibit GABAA neurons at the substania nigra. Also, when activated, cannabinoids primarily 2-archydonoglcerol, can indirectly disinhibit (red hash sign) GABAA neurons through activation of G1/0 coupled to CB1 receptors in the Substania Nigra. In the Dorsal Raphe Nuclei (DRN), glutamate neurons can then indirectly disinhibit GABAA neurons in the Substania Nigra through activation of GLU M3 receptors (red hash sign). GABAA neurons, when stimulated, will, in turn, powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB 3 neurons. It is also possible that stimulation of ACH neurons that at the Nucleus Accumbens ACH can stimulate both muscarinic (red hash) or Nicotinic (green hash). Finally, Glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (green equal sign)to preferentially release dopamine at the Nucleus Accumbens (NAc) shown as a bullseye indicates a euphoria, or “wanting” response. The result is that when dopamine release is low (endorphin deficiency), unhappiness is felt while general (healthy) happiness depends on the dopamine homeostatic tonic set point (see Fig. 2).

Fig. 2

A simple schematic of tonic happiness –set-point based on dopamine release, as explained in Fig. 1.

Fig. 3

Schematic of genetic and epigenetic induction of Opioid Peptide Deficiency Syndrome. Induction of an Opioid Peptide Deficiency Syndrome (OPDS) may involve both genetic and epigenetic insults to the brain reward circuitry specific to opioid peptides (i.e., endorphins, enkephalins, and dynorphins). Genetic deficits may include polymorphisms in the Membrane metal- endopeptidase (MME), a carboxypeptidase enzyme, responsible for the inactivation of endogenous opioid peptides. Comings et al. identified a dinucleotide polymorphism in the 5′ region of the MME gene that provides a high activity of this enzyme and subsequent reduced endogenous opioid peptides by strong inactivation. Consequently, a general “hypoopioidergia” or a specific “hypoendorphinergia” function at both the delta or mu receptors and a ‘hypodynophinergia” at kappa receptors (not shown in Fig. 3) [red hatch sign]. Also, at birth, an individual may carry the of the rs260997 C allele of Proenkephalin (PENK) which causes, significantly reduced enkephalin synthesis across the BRC [red hatch sign]. Moreover, Niikura et al. reported that there are epigenetic insults that reduce mRNA expression involving downregulation of mu receptor numbers or availability by chronic use/misuse of opiate analgesics, like heroin, or powerful synthetic opioids like methadone, buprenorphine, [red hatch sign]. Furthermore, Nylander et al. showed a reduced leu-enkephalin in the VTA of Sprague Dawley rats with chronic morphine treatment [red hatch sign] The dark green arrows represent the normal flow.