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Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
Learn More >Complex regional pain syndrome (CRPS) is a debilitating neuroinflammatory condition of unknown etiology. Symptoms include excruciating pain and trophic changes in the limbs as defined by the Budapest criteria. The severity and functional recovery of CRPS, unlike most pain conditions, is quantifiable using a variation of the Budapest criteria known as the CRPS severity score. Like many chronic pain conditions, CRPS is difficult to treat once pain has been present for more than 12 months. However, previous work has demonstrated that a subset of patients with new-onset CRPS (~50%) improve if treated within one year, while the rest have minimal to no symptom improvement. Unfortunately, this leads to permanent disability and often requires invasive and costly treatments such as spinal cord stimulation or long-term opioid therapy. Because the etiology is unknown, treatment is multimodal, and often supportive. Biomarkers that predict severity or resolution of symptoms would significantly change treatment but have not yet been identified. Interestingly, there are case reports of remission or resolution of CRPS symptoms with the use of antibiotics known to affect the gut flora. Mouse studies have demonstrated that modulation of the gut microbiome is anti-nociceptive in visceral, inflammatory and neuropathic pain models. We hypothesize that the variable clinical potential for recovery and response to therapy in CRPS may be secondary to or reflected in changes in the gut microbiota. We suggest that the microbiota may mediate or reflect clinical status via the metabolome, activation of the immune system and/or microglial activation. We hypothesize that the gut microbiome is a potential mediator in development and persistence of CRPS symptoms and propose that the clinical condition of CRPS could provide a unique opportunity to identify biomarkers of the microbiota and potential therapies to prevent pain chronification.
Learn More >Central amygdala (CeA) neurons expressing protein kinase Cδ (PKCδ) or somatostatin (Som) differentially modulate diverse behaviors. The underlying features supporting cell-type-specific function in the CeA, however, remain unknown. Using whole-cell patch-clamp electrophysiology in acute mouse brain slices and biocytin-based neuronal reconstructions, we demonstrate that neuronal morphology and relative excitability are two distinguishing features between Som and PKCδ neurons in the laterocapsular subdivision of the CeA (CeLC). Som neurons, for example, are more excitable, compact, and with more complex dendritic arborizations than PKCδ neurons. Cell size, intrinsic membrane properties, and anatomic localization were further shown to correlate with cell-type-specific differences in excitability. Lastly, in the context of neuropathic pain, we show a shift in the excitability equilibrium between PKCδ and Som neurons, suggesting that imbalances in the relative output of these cells underlie maladaptive changes in behaviors. Together, our results identify fundamentally important distinguishing features of PKCδ and Som cells that support cell-type-specific function in the CeA.
Learn More >Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative affective states. The transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Past work has identified the emergence of significant hyperalgesia/allodynia in alcohol-dependent animals, which may serve as a key negative reinforcement mechanism. Chronic pain has been associated with enhanced extracellular signal-regulated kinase (ERK) activity in cortical and subcortical nociceptive areas. Additionally, both pain and AUD have been associated with increased activity of the glucocorticoid receptor (GR), a key mediator of stress responsiveness. The objectives of the current study were to first determine relationships between thermal nociceptive sensitivity and alcohol drinking in male Wistar rats. While inflammatory pain induced by complete Freund's adjuvant (CFA) administration did not modify escalation of home cage drinking in animals over four weeks, the relationship between drinking levels and hyperalgesia symptoms reversed between acute (1 week) and chronic (3-4 week) periods post-CFA administration, suggesting that either the motivational or analgesic effects of alcohol may be altered over the time course of chronic pain. We next examined ERK and GR phosphorylation in pain-related brain areas (including the central amygdala and prefrontal cortex subregions) in animals experiencing acute withdrawal from binge alcohol administration (2 g/kg, 6 h withdrawal) and CFA administration (four weeks) to model the neurobiological consequences of binge alcohol exposure in the context of pain. We observed a significant interaction between alcohol and pain state, whereby alcohol withdrawal increased ERK phosphorylation across all four frontocortical areas examined, although this effect was absent in animals experiencing chronic inflammatory pain. Alcohol withdrawal also increased GR phosphorylation across all four frontocortical areas, but these changes were not altered by CFA. Interestingly, we observed significant inter-brain regional correlations in GR phosphorylation between the insula and other regions investigated only in animals exposed to both alcohol and CFA, suggesting coordinated activity in insula circuitry and glucocorticoid signaling in this context. The results of these studies provide a greater understanding of the neurobiology of AUD and will contribute to the development of effective treatment strategies for comorbid AUD and pain.
Learn More >To evaluate the association between adverse childhood experiences (ACEs) and chronic pain during childhood and adolescence.
Learn More >The aim of this study was to determine simple risk factors for severe pain intensity (≥7 points on a numeric rating scale [NRS]), to analyse their relation to other patient-reported outcome measures and to develop a simple prediction model.
Learn More >Naltrexone reversibly blocks the effects of opioids and has been shown to decrease placebo analgesia. However, it is not clear (1) to what extent naltrexone affects pain modulation in a nontreatment context, for example, in response to pain cues or (2) how naltrexone given prior to pain-cue learning shapes pain responses. In a double-blind procedure prior to pain-cue conditioning, 30 healthy participants were randomized to receive an oral dose of naltrexone (50 mg) or inert pill. During functional magnetic resonance imaging, high and low pain pressures were paired with two different visual cues: a high pain cue and a low pain cue (learning sequence). During a test sequence, medium levels of pressure were used for both cues and the difference in subjective pain ratings following high and low pain cues was calculated. Results showed significant conditioned pain responses across groups (<.001); however, no significant difference between participants receiving naltrexone or inert pill (=.193). There was a significant correlation between the difference in high and low pain ratings during the learning sequence and the effect of high and low pain cues during the test sequence (r = .575, =.002). Functional magnetic resonance imaging analyses revealed no significant difference in brain activation between groups. Here, we demonstrate comparable learning of pain responses in participants treated with naltrexone or inert pill. The results point to the possibility that associative learning, and conditional responding to pain cues, is not dependent on endogenous opioids. Our results, using pain-cue conditioning to create reduced pain responses, contrast previous studies where opioid antagonists significantly reduced the placebo effect in treatment of pain.
Learn More >Cancer pain is often treated with opioids, a therapeutic regimen that can become a challenge in patients with an opioid use disorder (OUD). While use of the buprenorphine-naloxone combination is an effective medication-assisted treatment (MAT) for OUD, its use in pain patients with OUD has been controversial due to concerns that co-administration of buprenorphine can reduce or block analge-sia and precipitate opioid withdrawal in those patients requiring full opioid agonists. Data on its use in cancer pain patients are lack-ing. In this case series, the authors explore the frequency of buprenorphine-naloxone use and its outcomes in patients in a Compre-hensive Care Center (CCC) Pain Registry. OUD was deduced from an International Classification of Diseases (ICD-10) diagnostic code for opioid-related disorders recorded in the electronic medical records. Of 2,320 chronic cancer pain patients, 125 patients had ICD-10 code for opioid-related disorders, and 43 had a diagnosis of opioid abuse of whom 11 received buprenorphine-naloxone combina-tions. Eight patients on 18 (6-24) mg per day of buprenorphine-naloxone remained in therapy for 4 (2-7) years without opioid abuse relapse. This assessment was based on clinician's notes, the Prescription Monitoring Program, random urine drug screening, and the absence of Urgent Care Center visits for opioid withdrawal or overdose. When short-term opioids were administered for acute pain, these patients were able to taper down and stop them quickly without an opioid abuse relapse. Buprenorphine-naloxone was effec-tive as the sole analgesic in selected patients. Given its success at the CCC, buprenorphine-naloxone should be made available and strongly considered as a treatment for patients suffering from OUD during and following cancer treatment and when cancer pain re-duces or resolves.
Learn More >Telomere length, a measure of cellular aging, is inversely associated with chronic pain severity. While psychological resilience factors (e.g., optimism, acceptance, positive affect, active coping) are associated with lower levels of clinical pain and greater physical functioning, it is unknown whether resilience may buffer against telomere shortening in individuals with chronic pain. Additionally, a broader conceptualization of resilience that includes social and biobehavioral factors may improve our understanding of the relationship between resilience, chronic pain, and health outcomes. In individuals with and without chronic knee pain, we investigated whether: 1) psychological resilience would be positively associated with telomere length, and if 2) a broader conceptualization of resilience including social and biobehavioral factors would strengthen the association. Seventy-nine adults, 45-85 years of age, with and without knee pain completed demographic, health, clinical pain, psychological, social, and biobehavioral questionnaires. Resilience levels were determining by summing the total number of measures indicating resilience based on published clinical ranges and norms. Blood samples were collected and telomere length determined. In regression analyses controlling for sex, race, age, and characteristic pain intensity, greater psychological resilience and psychosocial/biobehavioral resilience were associated with longer telomeres (p = .0295 and p = .0116, respectively). When compared, psychosocial/biobehavioral resilience was significantly more predictive of telomere length than the psychological resilience (p < .0001). Findings are promising and encourage further investigations to enhance understanding of the biological interface of psychosocial and biobehavioral resilience factors in individuals with musculoskeletal chronic pain conditions.
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