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Sensory neuron nicotinic acetylcholine receptors (nAChRs) contribute to pain associated with tissue injury. However, there are marked differences between rats and mice with respect to both the properties and distribution of nAChR currents in sensory neurons. Since both species are used to understand pain signaling in humans, we sought to determine whether the currents present in either species was reflective of those present in human sensory neurons. Neurons from lumbar 4/5 dorsal root ganglia were obtained from adult male and female organ donors. Nicotine-evoked currents were detected in 40 of 47 neurons (85%). In contrast to the naïve mouse, in which almost all nAChR currents are transient, or the rat, in which both mouse-like transient and more slowly activating and inactivating currents are detected, all the currents in human DRG neurons were slow, but slower than those in the rat. Currents were blocked by the nAChR antagonists mecamylamine (30 µM), but not by the TRPA1 selective antagonist HC-030031 (10µM). Single cell PCR analysis of nicotinic receptor subunit expression in human DRG neurons are consistent with functional data indicating that receptor expression is detected 85 ± 2.1% of neurons assessed (n = 48, from 4 donors). The most prevalent co-expression pattern was α3/β2 (95 ± 4% of neurons with subunits), but α7 subunits were detected in 70 ± 3.4% of neurons. These results suggest that there are not only species differences in the sensory neuron distribution of nAChR currents between rodent and human, but that the subunit composition of the channel underlying human nAChR currents may be different from those in the mouse or rat. PERSPECTIVE: The properties and distribution of nicotine-evoked currents in human sensory neurons were markedly different from those previously observed in mice and rats. These observations add additional support to the suggestion human sensory neurons maybe an essential screening tool for those considering moving novel therapeutics targeting primary afferents into clinical trials.
Learn More >To test the hypothesis that the effect of video consultations is noninferior to traditional consultations in managing patients with overuse headache (MOH).
Learn More >Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord. However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation. In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischemia are NO-dependent and that NO is produced by ischemia and quickly diffuses within the spinal cord. We also found that NO production induced by ischemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase-positive dorsal horn neurons express group II mGluRs. These results strongly suggest that NO-mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain.
Learn More >To inform migraine care model development by assessing differences between patients with chronic migraine (CM) and episodic migraine (EM) in the current state of treatment, disability, patient satisfaction, and quality improvement opportunities.
Learn More >Chronic postsurgical knee-pain (CPSP) is a burden for approx. 20% of the patients following total knee replacement (TKR). Presurgical pain intensities have consistently been found associated with CPSP and it is suggested that e.g. comorbidities are likewise important for development of CPSP. This study aimed to identify presurgical risk factors for development of CPSP 5 years after TKR based on medical records containing information regarding comorbidities.
Learn More >The descending nociceptive inhibitory pathways often malfunction in people with chronic pain. Conditioned pain modulation (CPM) is an experimental evaluation tool for assessing the functioning of these pathways. Spinal cord stimulation (SCS), a well-known treatment option for people with failed back surgery syndrome (FBSS), probably exerts its pain-relieving effect through a complex interplay of segmental and higher-order structures.
Learn More >While several studies have found that chronic pain is characterized by increased cross-network connectivity between salience, sensorimotor, and default mode (DMN) networks, a large sample-size investigation allowing a more reliable evaluation of somatotopic specificity and subgroup analyses with linkage to clinical pain intensity has been lacking. We enrolled healthy adults and a large cohort of patients (N=181) suffering from chronic low back pain (cLBP). To specifically link brain connectivity with clinical pain intensity, patients were scanned at baseline and after performing physical maneuvers that exacerbated pain. Compared to healthy adults, cLBP patients demonstrated increased connectivity between the functionally-localized back representation in primary somatosensory cortex (S1back) and both salience and DMN networks. Pain exacerbation maneuvers increased S1back connectivity to salience network regions, but decreased connectivity to DMN, with greater pain intensity increase associated with greater shifts in these connectivity patterns. Furthermore, only in cLBP patients reporting high pain catastrophizing, DMN connectivity was increased to a cardinal node of the salience network, anterior insula cortex, which was correlated with increased post-maneuver pain in this cLBP subgroup. Hence, increased information transfer between salience processing regions, particularly anterior insula, and DMN may be strongly influenced by pain catastrophizing. Increased information transfer between salience network and S1 likely plays an important role in shifting nociceptive afference away from self-referential processing, re-allocating attentional focus and affective coding of nociceptive afference from specific body areas. These results demonstrate S1 somatotopic specificity for cross-network connectivity in encoding clinical back pain, and moderating influence of catastrophizing for DMN/insula connectivity.
Learn More >Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS.
Learn More >Parents play a critical role in children's experience of, and recovery from, chronic pain. Although several parental factors have been linked to child pain and functioning, these factors are typically examined in isolation or as moderators/mediators. Structural equation modeling affords the opportunity to examine the extent to which parental factors are interrelated, and if there are differential associations among parental factors and child outcomes. Based on extant literature, a unified model of parental factors, including chronic pain status, physical functioning, responses to child pain, and psychological factors, and their effect on child pain and functioning, was conceptualized. This model was evaluated using structural equation modeling based on data from 146 dyads recruited from a multidisciplinary pain clinic. Modifications to model iterations were made based on theoretical and statistical justification. The final model revealed associations among all parental factors with significant loadings on child pain and functioning. Findings indicated the conceptual model was supported, with the exception of parent responses to child pain. Findings support inclusion of parent chronic pain status and physical and psychological functioning as part of a comprehensive assessment of youth with chronic pain and may inform new parental intervention targets to improve child outcomes. Perspective: A unified structural equation model indicated parents' own chronic pain characteristics and physical and psychological functioning represent important factors associated with child pain and functioning. Current family-based interventions which often primarily focus on parent responses to child pain may need to be adapted to more comprehensively address parental factors.
Learn More >The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.
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