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It has recently been shown that epidermal growth factor receptor (EGFR) contributes to the pathogenesis of pain. We scanned genetic markers within genes coding for receptors of the EGFR family (EGFR, ERBB2, ERBB3 and ERBB4) and their ligands (AREG, BTC, EGF, EPGN, EREG, HBEGF, MUC4, NRG1, NRG2, NRG3, NRG4 and TGFA) for association with self-reported pain intensity in patients with chronic facial pain who participated in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. We found that only epiregulin (EREG) was associated with pain. The strongest effect was observed for a minor allele at rs6836436 in EREG, which was associated with lower chronic pain intensity. However, the same allele was associated with higher facial pain intensity among cases with recent onset of facial pain. Similar trends were observed in an independent cohort of UK Biobank (UKB) where the minor allele at rs6836436 was associated with a higher number of acute pain sites but a lower number of chronic pain sites. Expression quantitative trait loci (eQTL) analyses established rs6836436 as a loss-of-function variant of EREG. Lastly, we investigated the functional role of epiregulin using mouse models of chronic and acute pain. Injecting mice with an EREG monoclonal antibody (mAb) reversed established mechanosensitivity in the complete Freund's adjuvant (CFA) and spared nerve injury (SNI) models of chronic pain. However, the EREG mAb prolonged allodynia when administered during the development of CFA-induced mechanosensitivity and enhanced pain behavior in the capsaicin model of acute pain.
Learn More >This proposed systematic review will identify the existing evidence on medication-overuse headache in children and adolescents.
Learn More >Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks (RSNs) and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in TSOP and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with: 1) stronger rsFCs of the posterior cingulate cortex (PCC), with the ventromedial prefrontal cortex (vmPFC) and with the pregenual anterior cingulate cortex (pgACC); 2) weaker rsFC of the anterior insula with the angular gyrus. However, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine. Perspective: This article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in heath and in the presence of chronic pain.
Learn More >Learning through social observation is critical for humans. The present study investigates the neural processes underlying the acquisition of placebo effects through observational learning. We created a new functional magnetic resonance imaging (fMRI) paradigm where participants (n = 38, healthy, both sexes) observed a demonstrator experiencing pain relief by a placebo treatment cream and experiencing pain without a treatment (control cream), and subsequently performed the same procedure themselves. Participants demonstrated placebo hypoalgesia while they performed the procedure themselves, confirming that observational learning can lead to placebo effects. During the observational learning phase, fMRI analysis showed a modulation of the amygdalae, periaqueductal grey, temporoparietal junctions (TPJ), and dorsolateral prefrontal cortex (DLPFC). Connectivity between the DLPFC and TPJ during the observational learning task was modulated by the placebo treatment and predicted subsequent placebo effects. Mediation analysis further confirmed that the DLPFC-TPJ connectivity formally mediated the effect of the observed treatment condition on subsequent placebo effects. Additionally, pre-recorded resting state connectivity between the DLPFC and TPJ also predicted observationally-learned placebo effects. Our findings provide an understanding of the neural processes during the acquisition of placebo effects through observation and indicate a critical role for DLPFC-TPJ integration processes during observational learning of therapeutic outcomes.
Learn More >Engaging in altruistic behaviors is costly, but it contributes to the health and well-being of the performer of such behaviors. The present research offers a take on how this paradox can be understood. Across 2 pilot studies and 3 experiments, we showed a pain-relieving effect of performing altruistic behaviors. Acting altruistically relieved not only acutely induced physical pain among healthy adults but also chronic pain among cancer patients. Using functional MRI, we found that after individuals performed altruistic actions brain activity in the dorsal anterior cingulate cortex and bilateral insula in response to a painful shock was significantly reduced. This reduced pain-induced activation in the right insula was mediated by the neural activity in the ventral medial prefrontal cortex (VMPFC), while the activation of the VMPFC was positively correlated with the performer's experienced meaningfulness from his or her altruistic behavior. Our findings suggest that incurring personal costs to help others may buffer the performers from unpleasant conditions.
Learn More >The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD).
Learn More >Recent insights into the clinical presentation and pathophysiology of migraine aura have paved the way for new treatments for this common but frequently debilitating condition. Marked efflux of cellular potassium and glutamate contributes to the cortical spreading depression that forms the electrophysiological basis of migraine aura phenomena. Secondary vascular perturbations also contribute to the various symptoms of a migraine attack. Calcitonin gene-related peptide (CGRP) plays a key role in many of these steps, and a growing class of CGRP-antagonists have emerged as a novel, efficacious preventative therapy. It is still not fully understood why a preponderance of migraine aura symptoms is visual, and this issue is an active area of research. In addition, the pathophysiological changes responsible for visual snow syndrome are under investigation. Before diagnosing a patient with migraine aura, it is important to consider the differential diagnosis of transient visual phenomena, with attention to clinical features that may suggest conditions such as retinal disorders, transient ischemic attack, or occipital epilepsy.
Learn More >Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several the pore-forming voltage-gated sodium channel α subunits (Nas) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β subunits modulate Na trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the β2-subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly-identified Y69H variant of the β2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans.
Learn More >Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.
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