Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission.

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.

Pain Management for Dental Medicine in 2021: Opioids, Coronavirus and Beyond.

Over the past year our attention has inevitably been on the coronavirus pandemic, the health and welfare of our families, patients, and office staffs as well as the re-opening of our dental practices. In addition, the opioid crisis continues, is very likely to worsen as a result of the pandemic and continues to be a challenge to Dentistry. National public health issues and healthcare disparities continue and have created a global concern for providing evidence-based, adequate pain management in the dental setting.

Role of the Prefrontal Cortex in Pain Processing.

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.

Role of prefrontal cortical calcium-independent phospholipase A in antinociceptive effect of the norepinephrine reuptake inhibitor antidepresssant maprotiline.

The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A (iPLA) in antinociception induced by the norepinephrine reuptake inhibitor (NRI) and tetracyclic (tricyclic) antidepressant, maprotiline.

Chronic Back Pain Is Associated with Alterations in Dopamine Neurotransmission in the Ventral Striatum.

Unlabelled: Back pain is common in the general population, but only a subgroup of back pain patients develops a disabling chronic pain state. The reasons for this are incompletely understood, but recent evidence implies that both preexisting and pain-related variations in the structure and function of the nervous system may contribute significantly to the development of chronic pain. Here, we addressed the role of striatal dopamine (DA) D2/D3 receptor (D2/D3R) function in chronic non-neuropathic back pain (CNBP) by comparing CNBP patients and healthy controls using PET and the D2/D3R-selective radioligand [(11)C]raclopride.

Effects of the Mu opioid receptor polymorphism (OPRM1 A118G) on pain regulation, placebo effects and associated personality trait measures.

Mu-opioid receptors (MOPRs) are critically involved in the modulation of pain and analgesia, and represent a candidate mechanism for the development of biomarkers of pain conditions and their responses to treatment. To further understand the human implications of genetic variation within the opioid system in pain and opioid-mediated placebo responses, we investigated the association between the functional single-nucleotide polymorphism (SNP) in the μ-opioid receptor gene (OPRM1), A118G, and psychophysical responses, personality traits, and neurotransmitter systems (dopamine (DA), opioid) related to pain and placebo analgesia. OPRM1 G carriers, compared with AA homozygotes, showed an overall reduction of baseline μ-opioid receptor availability in regions implicated in pain and affective regulation.

Dynamic interactions between plasma IL-1 family cytokines and central endogenous opioid neurotransmitter function in humans.

Evidence in animal models suggests IL-1 family cytokines interact with central endogenous opioid neurotransmitter systems, inducing or perpetuating pathological states such as persistent pain syndromes, depression, substance use disorders, and their comorbidity. Understanding these interactions in humans is particularly relevant to understanding pathological states wherein this neurotransmitter system is implicated (ie, persistent pain, mood disorders, substance use disorders, etc). Here, we examined relationships between IL-1β, IL-1ra, and functional measures of the endogenous opioid system in 34 healthy volunteers, in the absence and presence of a standardized sustained muscular pain challenge, a psychophysical challenge with emotionally and physically stressful components.

Valence-specific effects of BDNF Val66Met polymorphism on dopaminergic stress and reward processing in humans.

Brain-derived neurotrophic factor (BDNF) levels in dopaminergic (DA) cells within the ventral tegmental area (VTA)/nucleus accumbens (NAc) circuitry appear to be a candidate mechanism for the neuroadaptive changes that follow stress and reward responses in animal models. However, the role of the BDNF gene variants in responses to salient cues through DA neurotransmission in humans remains unexplored. Here, we studied the effect of the common functional BDNF Val(66)Met (rs6265) polymorphism on rewarding experiences in the striatum and DA-mediated responses to stress.

Alterations in endogenous opioid functional measures in chronic back pain.

The absence of consistent end organ abnormalities in many chronic pain syndromes has led to a search for maladaptive CNS mechanisms that may explain their clinical presentations and course. Here, we addressed the role of brain regional μ-opioid receptor-mediated neurotransmission, one of the best recognized mechanisms of pain regulation, in chronic back pain in human subjects. We compared μ-opioid receptor availability in vivo at baseline, during pain expectation, and with moderate levels of sustained pain in 16 patients with chronic nonspecific back pain (CNBP) and in 16 age- and gender-matched healthy control subjects, using the μ-opioid receptor-selective radioligand [(11)C]carfentanil and positron emission tomography.

Neurobiology of placebo effects: expectations or learning?

Contemporary learning theories suggest that conditioning is heavily dependent on the processing of prediction errors, which signal a discrepancy between expected and observed outcomes. This line of research provides a framework through which classical theories of placebo effects, expectations and conditioning, can be reconciled. Brain regions related to prediction error processing [anterior cingulate cortex (ACC), orbitofrontal cortex or the nucleus accumbens] overlap with those involved in placebo effects.

Personality trait predictors of placebo analgesia and neurobiological correlates.

Personality traits have been shown to interact with environmental cues to modulate biological responses including treatment responses, and potentially having a role in the formation of placebo effects. Here, we assessed psychological traits in 50 healthy controls as to their capacity to predict placebo analgesic effects, placebo-induced activation of μ-opioid neurotransmission and changes in cortisol plasma levels during a sustained experimental pain challenge (hypertonic saline infused in the masseter muscle) with and without placebo administration. Statistical analyses showed that an aggregate of scores from Ego-Resiliency, NEO Altruism, NEO Straightforwardness (positive predictors) and NEO Angry Hostility (negative predictor) scales accounted for 25% of the variance in placebo analgesic responses.

Leptin regulates dopamine responses to sustained stress in humans.

Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge.

Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans.

Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders.

DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience.

Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine inter-individual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation.

Oxytocin gene polymorphisms influence human dopaminergic function in a sex-dependent manner.

Background: Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin's interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample.

Comprehensive gene expression profiling in the prefrontal cortex links immune activation and neutrophil infiltration to antinociception.

Functional neuroimaging studies have implicated the prefrontal cortex (PFCTX) in descending modulation of pain and the placebo effect. This study was performed to elucidate comprehensive PFCTX gene expression in an animal model of persistent trigeminal pain. Adult male C57BL/6J mice received facial carrageenan injection and showed sustained increase in nociceptive responses.

Emotion processing, major depression, and functional genetic variation of neuropeptide Y.

Context: Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion.

Pain imaging in the emerging era of molecular medicine.

With the dawn of the twenty-first Century, imaging has assumed a new role in disease-oriented science. Regarding pain, the emphasis clearly turned from structural to functional imaging with functional molecular imaging assuming the leading edge. This trend parallels the efforts of biologists working to understand the molecular messages of cell and cell systems relevant to human disease processes.

Positron emission tomography measures of endogenous opioid neurotransmission and impulsiveness traits in humans.

Context: The endogenous opioid system and opioid mu receptors (mu-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 mu-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 mu-receptor-selective radiotracer carfentanil labeled with carbon 11.

Neurobiological mechanisms of placebo responses.

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, potentially impacting perceptions and biological processes. We used sustained pain as a model to determine the neural mechanisms underlying placebo-induced analgesia and affective changes in healthy humans.