Transmodulation of Dopaminergic Signaling to Mitigate Hypodopminergia and Pharmaceutical Opioid-Induced Hyperalgesia

1.1. Background

There is ample evidence that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and medulla. However, pain sensitivity may be controlled by additional neurological loci, especially in the mesolimbic system of the brain (the reward center). Several genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. The hypothesis is that these polymorphisms associate with a predisposition to pain intolerance or tolerance. Further, the identification of specific gene polymorphisms may provide a novel therapeutic target for pain treatment. The hypothesis is that pharmacogenetic testing of particular candidate genes, for example, PENK, and mu receptors, will result in personalized solutions, with the potential for improvement in clinical outcomes. Genetically guided transmodulation of addiction risks polymorphisms using the pro-dopamine regulator, the precision neuro-nutrient (KB220) [1] could be combined with pharmaceutical opioid analgesic agents to mitigate hyperalgesia induced by hypodopaminergia [2–8].

Individuals tend to respond differently to medications and specific nutraceuticals, in terms of both toxicity and treatment efficacy [9]. Inherited differences in the metabolism and disposition of drugs and nutrients, and genetic variants (polymorphisms) in the drug and neuronutrient targets (such as the dopamine D2 receptor), can have a substantial influence on the clinical effectiveness and the toxicity of medications and nutraceuticals [10]. Indeed, without accurate gene-based prescreening, and subsequent supplementation, efficacy may be unpredictable. Like the pharmaceutical industry, the nutraceutical industry can initiate ongoing research and incorporate genome-based formulations as described herein. Information on genetic polymorphisms in genes that code for the enzymes, receptors and transporters related to opioid disposition (pharmacokinetics) and pharmacology (pharmacodynamics) is documented [11]. Pharmacogenetics of various enzymes, including the cytochrome P450s and uridine diphosphoglucuronosyltransferases, opioid receptors, and the ABC family of transporters, are a few examples.

1.2. Role of Mesolimbic Systems in Pain Control

The suppression of tonic pain involves various systems in addition to those known to suppress phasic pain, and these systems appear to include forebrain sites and those rostral to the brainstem. Interestingly, both psychostimulants and opioids decrease tonic pain while increasing transmission in the mesocorticolimbic dopaminergic neurons associated with natural rewards such as sex and food. These specific neurons originate from cell bodies such as the nucleus accumbens (NAc) within the ventral tegmental area (VTA), and the amygdala. They cross talk, via functional connectivity, with the prefrontal cortex forebrain loci. Moreover, projections from the NAc and amygdala (probably central nucleus) ascend to the limbic forebrain via the medial forebrain bundle.

Opioids indirectly activate these neurons and induce the release of dopamine [12]. Moreover, opioids have more rewarding and analgesic effects in clinical settings. Dopamine-depleting 6-hydroxydopamine lesions within the ventral midbrain, the very cells that contain the cell bodies of the neurons for the emergence of ascending forebrain projections, blocked the analgesic effects of systemic morphine in the formalin inflammatory test in animals. This finding of Morgan and Franklin [13] provided the first evidence for the role of mesolimbic dopamine neurons essential in the suppression of tonic pain. Taylor et al. [14] also revealed that the D1-selective agonist SKF38393 was without effect, specifically at a dose of 0.5 nmol/side, whereas the D2-selective agonist quinpirole dose-dependency (0.05–5.0 nmol/side, bilateral) inhibited the persistent phase of formalin-induced nociception. It is noteworthy that the D2 effect was antagonized by pretreatment with the selective D2-dopaminergic antagonist raclopride. Although an inability to fully activate the D1 receptors could be due to an effect of this agent, these results suggest that dopamine agonists specific to D2 receptors in the NAc inhibit inflammatory pain.

1.3. Dopamine D2 Receptors and Chronic Pain

Even before the seminal discovery of the opioid receptor, as well as endogenous opioid peptides, early studies by several laboratories devoted efforts to show the biochemical commonality of opioids and alcohol specific to dopamine condensation products. Tetrahydropapaveroline is a benzyltetrahydroisoquinoline alkaloid derivative of the biogenic amine, dopamine. Alcohol, by way of its primary metabolite, acetaldehyde, competitively inhibits nicotinamide-adenine Dinucleotide-linked aldehyde dehydrogenase and augments the formation of Tetrahydropapaveroline in vitro [15–21].

As seen in animal studies subcortical stria, as well as, cortical dopaminergic systems, participate in neural pain signal modulation and transmission. Dopamine D2 receptors mediate the inhibitory role of dopamine in animal models for persistent pain [22]. Hagelberg et al. [23] reported that high D2 receptor availability within the putamen of healthy participants is associated with low cold pain threshold and a conditioned high pain modulation capacity. Of note, this effect involves mu receptor interaction [24]. Alterations seen on PET scan within the striatal dopaminergic system involved in chronic orofacial pain conditions show increased D2 receptor availability in the left hemisphere of the putamen and a decreased D1/D2 ratio [23].

Psychoactive drugs exert their initial reinforcing effects by triggering supraphysiologic surges of dopamine in the nucleus accumbens that activate the direct striatal pathway via D1 receptors and inhibit the indirect striato-cortical pathway via D2 receptors [25]. Thus, the relative expression of the D1/D2 ratio yields a differential modulation of the activity of mu receptor.

1.4. Stress and Dopamine and Pathophysiology of Chronic Pain

The relationship between stress, endorphins, and the hypothalamic-pituitary-adrenal (HPA) axis is well established [26]. Polymorphisms in the dopamine D2 receptor correlate with stress-coping mechanisms [27]. The bottom line is that stress can induce a painful condition, or it can exacerbate the pain. Deutch et al., based on their investigations, suggested that exposure to stress also activates dopamine transmission in mesocorticolimbic dopamine neurons [28], and even more striking this effect appears to involve opioid mechanisms in the VTA.

It is noteworthy that intra-VTA infusions of the opioid receptor antagonist Naltrexone prevent the stress-induced activation of dopamine metabolism in the reward center of the brain, specifically the NAc and prefrontal cortex. Also, exposure to stress causes the release of met-enkephalin into the VTA [29], which provides natural analgesic properties. Thus, exposure to stress may inhibit tonic pain. This exposure and the intra-VTA morphine-induced analgesia, as shown with the formalin test, implies that the endogenous release of opioids within the VTA might be a mechanism underlying the stress-induced inhibition of tonic pain. Also, intra-VTA infusions of the opioid receptor antagonist, naltrexone, attenuate stress-induced analgesia in the formalin test supports this finding [29].

The gate pain control theory, as first proposed Melzack & Wall [30] in 1965, was that sensory input from the skin is modulated by a gate system before perception and response to pain. Indeed, stress-induced inflammation, and its negative role in pain perception, are established. Altier et al., in a series of experiments [31, 32], suggested that the neuronal release of substance P (SP), the tachykinin neuropeptide, in the VTA could play a similar role in the stress-induced suppression of tonic pain. Altier et al. [32] found that activation of midbrain dopamine neurons by SP did indeed inhibit tonic pain in the formalin test, suggesting a role for dopamine. Finally, exposure to stress induces analgesia by causing a release of SP in the VTA, which in turn, activates mesocorticolimbic dopamine neurons. Of interest is the psychopharmacological effect that opioids, and SP share; the ability to augment dopamine release in the NAc. Also, opioids administered systemically or into the VTA enhance dopamine metabolism and extracellular levels of dopamine in the NAc.

2.1. A Snapshot

It is well-known that humans react differently to opioids. A specific opioid such as morphine sulfate may have specific analgesic effects for individual patients with, for example, postherpetic neuralgia, whereas other patients with the same problem may experience quite different analgesic qualities. These differing effects could occur for any pain condition and any pharmaceutical analgesic agent such as opioids and anti-inflammatory compounds. These differences may be due to both pharmacokinetic and pharmacodynamic differences and other unknown factors. Clinicians, in the past, were not able to predict which patients will respond well or poorly to various opioids. In more recent times, the scientific community, through very sophisticated research, has unraveled pharmacogenetic information about specific neurogenetic aspects of opioid-induced analgesic mechanisms. These novel discoveries involved different genetics, biochemical, and receptor interaction of opioids in humans. Even more exciting is the specific knowledge gleaned from databases on knockout rodents, pharmacogenetics, and gene polymorphisms. The development of the Genetic Addiction Risk Score (GARS) and related research [33–37], if adopted by the pain community, will have a significant impact on the ability of clinicians to predict patient responses to doses of specific opioids in their efforts to individualize optimal opioid analgesic therapy. Prudent utilization of the GARS test offers Primary Care and Pain Physicians, an opportunity with additional genetic information to become more adept at tailoring appropriate opioid treatment as well as optimal opioid rotation strategies.

Specific candidate genes such as those for catechol-O-methyl-transferase, and possibly in the future melanocortin-1 receptor, guanosine triphosphate cyclohydrolase, and the mu-opioid receptor, were studied intensively, and associations found with analgesic requirements in states of acute and chronic pain and sensitivity to pain [38–43].

2.2. Classification of Gene Polymorphisms as Risk

To assist in the rationale utilized for each listed risk allele, we relied on the extensive literature review. The driving force behind the selection of the various alleles, despite the controversy, was the unifying concept that each allele will result in a lowered dopaminergic function. Table 1 provides the basis for each selection.

The following represents the development of the first genetic addiction risk score for RDS behaviors, specifically alcohol and drugs. The genetic risk score utilized in the current study captures genetic variation in the brain reward cascade.

Table 1 presents the current GARS SNPs and genes involved in testing as developed in the Genomic Testing Center of Geneus Health.

In essence, we hypothesize that low or hypodopaminergic function in the brain may predispose individuals to low pain tolerance or hyperalgesia. Current research supports this theory, and thus carriers of the D2 TaqA1 allele as observed in RDS [44] may be good candidates for nutrients or bioactive substances designed to enhance dopamine release in the brain while reducing unwanted hyperalgesia.