The prefrontal cortex (PFC) is not only important in executive functions, but also pain processing. The latter is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray (PAG), thalamus, amygdala, and basal nuclei. Changes in neurotransmitters, gene expression, glial cells, and neuroinflammation occur in the PFC during acute and chronic pain, that result in alterations to its structure, activity, and connectivity. The medial PFC (mPFC) could serve dual, opposing roles in pain: (1) it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain. This is a 'loop' where, on one side, a sensory stimulus is transformed into a perceptual signal through high brain processing activity, and perceptual activity is then utilized to control the flow of afferent sensory stimuli at their entrance (dorsal horn) to the CNS. (2) It could induce pain chronification via its corticostriatal projection, possibly depending on the level of dopamine receptor activation (or lack of) in the ventral tegmental area-nucleus accumbens reward pathway. The PFC is involved in biopsychosocial pain management. This includes repetitive transcranial magnetic stimulation, transcranial direct current stimulation, antidepressants, acupuncture, cognitive behavioral therapy, mindfulness, music, exercise, partner support, empathy, meditation, and prayer. Studies demonstrate the role of the PFC during placebo analgesia, and in establishing links between pain and depression, anxiety, and loss of cognition. In particular, losses in PFC grey matter are often reversible after successful treatment of chronic pain.
Abstract Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain μ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11 C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BP ND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W 74 = −3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T 148 = 3.33; p uncorr < 0.001) and left amygdala (T 148 = 3.30; p uncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.
As major academic institutions are making huge financial investments to embrace the vision of precision medicine, it appears timely to reflect upon the prospects of aligning the range of disease conditions covered by this journal with the goal of a smarter, individualized medicine, yielding a greater chance of benefit to a particular patient while reducing the likelihood of encountering unwanted effects and complications. Delivering treatments in a way that is smarter than current practice holds the prospect of reducing health care cost in the long run. To best capture the operational framework of what is about to happen, Margaret Hamburg and Francis Collins have stated: “When the federal government created the national highway system, it did not tell people where to drive—it built the roads and set the standards for safety. Those investments supported a revolution in transportation, commerce, and personal mobility. We are now building a national highway system for personalized medicine, with substantial investments in infrastructure and standards. We look forward to doctors’ and patients’ navigating these roads to better outcomes and better health.”¹
The path to reach the point at which we will be able to offer an individualized treatment for “Mrs Jones” depends to a large degree on the type of condition experienced. For the rarest presentations, the genotype alone may yield useful information for the clinician in support of individualizing care. But for the more common diseases, the identification of valid biomarkers that support clinical decisions to define a “personalized/precise” approach for Mrs Jones represents a scientific challenge. The complex nature of their etiopathogenesis, including the multitude of mechanistic variations—not just two or three— producing an array of clinically similar symptoms, calls for the study of individual variations among cases and the degree to which specific variations contribute to the clinical picture. Elucidating this web may require sample sizes in excess of 20,000 subjects to reach reasonable confidence in the reported findings.
Today we have good reasons to group the common, persistent orofacial pain conditions in terms of their complex etiopathogenesis with chronic conditions such as obesity, diabetes, depression, hypertension, and many others. A personalized treatment strategy will need to consider genetics and environmental influences with effects that may even be inherited from one generation to the next but not associated with changes in the DNA sequence. It will also need to consider riskconferring behaviors, varying in their individual effect among clinical cases. Unraveling this mechanistic complexity will be the scientific challenge ahead.
The perception of “bodily dysfunction” is a personal matter that shapes much of how and to what degree symptom severity is felt and reported. It is now established that common genetic variants are associated with variations in brain function, which in turn can be linked to personality traits, behavioral phenotypes, and emotional states. Each of the genetic and epigenetic variants, including their interactions, can either amplify or attenuate the expression of the perceived state of dysfunction reported and measured clinically. The path to precision and personalized medicine will have to identify and take into account those individually applicable genetic and epigenetic variants that amplify to a significant degree the perceived and observed state of disease and treatment response.
Precision medicine hinges on individual test results that promise a significantly better outcome for a given patient with a specific intervention when compared with other types of treatment. There is increasing awareness that the exploitation of perceptual profiles yields important clues, as genetic variants linked to the function of calcium channels, adrenaline, neurotrophic factors, dopamine, opiates, neuropeptide Y, and serotonin influence processes associated with the perception of symptoms and, to a lesser degree, the clinical manifestation of bodily dysfunction. While amazing results are attainable in the very near future for very rare diseases that are identifiable by the genetic code, acknowledging the complexity of the etiopathogenesis in effect in common diseases makes it clear that the roadway to precision medicine is in need of a “navigation tool” as inferred in the quote by Hamburg and Collins,1 cited above. Navigating the scientific discovery for the field that is represented by this journal in order to mine the avenues of precision medicine will require the dissection of the high-level case definitions that are based on symptoms and clinically observable signs to the study of low-level, intermediate phenotypes, markers of vulnerability, and subclinical traits that may or may not result in clinic cases.
The endogenous opioid system and opioid μ receptors (μ-receptors) are known to interface environmental events, positive (eg, relevant emotional stimuli) and negative (eg, stressors), with pertinent behavioral responses and to regulate motivated behavior.
Objective
To examine the degree to which trait impulsiveness (the tendency to act on cravings and urges rather than to delay gratification) is predicted by baseline μ-receptor availability or the response of this system to a standardized, experientially matched stressor.
Design, Setting, and Patients
Nineteen young healthy male volunteers completed a personality questionnaire (NEO Personality Inventory, Revised) and underwent positron emission tomography scans with the μ-receptor–selective radiotracer carfentanil labeled with carbon 11. Measures of receptor concentrations were obtained at rest and during receipt of an experimentally maintained pain stressor of matched intensity between subjects.
Main Outcome Measures
Baseline receptor levels and stress-induced activation of μ-opioid system neurotransmission compared between subjects scoring above and below the population median on the NEO Personality Inventory, Revised, impulsiveness subscale and the orthogonal dimension (deliberation) expected to interact with it.
Results
High impulsiveness and low deliberation scores were associated with significantly higher regional μ-receptor concentrations and greater stress-induced endogenous opioid system activation. Effects were obtained in the prefrontal and orbitofrontal cortices, anterior cingulate, thalamus, nucleus accumbens, and basolateral amygdala—all regions involved in motivated behavior and the effects of drugs of abuse. Availability of the μ-receptor and the magnitude of stress-induced endogenous opioid activation in these regions accounted for 17% to 49% of the variance in these personality traits.
Conclusions
Individual differences in the function of the endogenous μ-receptor system predict personality traits that confer vulnerability to or resiliency against risky behaviors such as the predisposition to develop substance use disorders. These personality traits are also implicated in psychopathological states (eg, personality disorders) in which variations in the function of this neurotransmitter system also may play a role.
The catechol-O-methyl-transferase (COMT) gene regulates the metabolic processes of the neurotransmitter dopamine and, through it, influences endorphins, which play an important role in the process of pain perception. It was found that the COMT gene with the amino acid valine (val158) is more active than the variant of the gene containing methionine (met158).
