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Chronic pain patients frequently suffer from psychological symptoms. There is no consensus concerning the prevalence of severe anxiety and depressive symptoms and the strength of the associations between pain intensity and psychological distress. Although an important aspect of the clinical picture is understanding how the pain condition impacts life, little is known about the relative importance of pain and psychological symptoms for individual's life impact. The aims of this study were to identify subgroups of pain patients; to analyze if pain, psychological distress, and life impact variables influence subgrouping; and to investigate how patients in the subgroups benefit from treatments.
Learn More >Neuropathic pain represents a primary detrimental outcome of spinal cord injury. A major challenge facing effective management is a lack of surrogate measures to examine the physiology and anatomy of neuropathic pain. To this end, we investigated the relationship between psychophysical responses to tonic heat stimulation and neuropathic pain rating after traumatic spinal cord injury. Subjects provided a continuous rating to 2 min of tonic heat at admission to rehabilitation and again at discharge. Adaptation, temporal summation of pain, and modulation profile (i.e., the relationship between adaptation and temporal summation of pain) were extracted from tonic heat curves for each subject. There was no association between any of the tonic heat outcomes and neuropathic pain severity at admission. The degree of adaptation, the degree of temporal summation of pain, and the modulation profile did not change significantly from admission to discharge. However, changes in modulation profiles between admission and discharge were significantly correlated with changes in neuropathic pain severity ( = 0.027; = 0.323). The modulation profile may represent an effective measure to track changes in neuropathic pain severity from early to later stages of spinal cord injury.
Learn More >Neuropathic pain resulting from peripheral nerve lesions is a common medical condition, but current analgesics are often insufficient. The identification of key molecules involved in pathological pain processing is a prerequisite for the development of new analgesic drugs. Hyperexcitability of nociceptive DRG-neurons due to regulation of voltage-gated ion-channels is generally assumed to contribute strongly to neuropathic pain. There is increasing evidence, that T-type Ca-currents and in particular the Ca3.2 T-type-channel isoform play an important role in neuropathic pain, but experimental results are contradicting.
Learn More >Chronic abdominal pain is the most common gastrointestinal issue and contributes to the pathophysiology of functional bowel disorders and inflammatory bowel disease. Current theories suggest that neuronal plasticity and broad alterations along the brain-gut axis contribute to the development of chronic abdominal pain, but the specific mechanisms involved in chronic abdominal pain remain incompletely understood. Accumulating evidence implicates glial cells in the development and maintenance of chronic pain. Astrocytes and microglia in the central nervous system and satellite glia in dorsal root ganglia contribute to chronic pain states through reactive gliosis, the modification of glial networks, and the synthesis and release of neuromodulators. In addition, new data suggest that enteric glia, a unique type of peripheral glia found within the enteric nervous system, have the potential to modify visceral perception through interactions with neurons and immune cells. Understanding these emerging roles of enteric glia is important to fully understand the mechanisms that drive chronic pain and to identify novel therapeutic targets. In this review, we discuss enteric glial cell signaling mechanisms that have the potential to influence chronic abdominal pain.
Learn More >Increasing evidence has suggested that central plasticity plays a crucial role in the development and maintenance of (chronic) nonspecific low back pain. However, it is unclear how local or short-distance functional interactions contribute to persisting low back-related leg pain (LBLP) due to a specific condition (i.e., lumbar disc herniation). In particular, the multiscale nature of local connectivity properties in various brain regions is still unclear. Here, we used voxelwise Kendall's coefficient of concordance (KCC) and coherence (Cohe) regional homogeneity (ReHo) in the typical (0.01-0.1 Hz) and five specific frequency (slow-6 to slow-2) bands to analyze individual whole-brain resting-state functional magnetic resonance imaging scans in 25 persistent LBLP patients (duration: 36.7 ± 9.6 months) and 26 healthy control subjects. Between-group differences demonstrated significant alterations in the KCC- and Cohe- ReHo of the right cerebellum posterior lobe, brainstem, left medial prefrontal cortex and bilateral precuneus in LBLP patients in the typical and five specific frequency bands, respectively, along with interactions between disease status and the five specific frequency bands in several regions of the pain matrix and the default-mode network (P < .01, Gaussian random field theory correction). The altered ReHo in the five specific frequency bands was correlated with the duration of pain and two-point discrimination, which were assessed using partial correlational analysis. These results linked the course of disease to the local connectivity properties in specific frequency bands in persisting LBLP. In future studies exploring local connectome association in pain conditions, integrated frequency bands and analytical methods should be considered.
Learn More >Conventional opioids are widely used for acute pain management in the postoperative setting. However, a primary concern with conventional opioids is their therapeutic window-the range between doses that produce the desired therapeutic effect (analgesia) and doses that produce unwanted opioid-related adverse events (ORAEs). Conventional µ receptor opioids have a narrow therapeutic window in part because of their mechanism of action (MoA): they bind to µ receptors and non-selectively activate two intracellular signaling pathways, leading to analgesia and to ORAEs. This review explores the clinical potential of µ receptor ligands with differential signaling. Agents with a 'differential signaling" MoA represent an innovative approach that may enhance the therapeutic window. These agents modulate µ receptor activity to selectively engage downstream signaling pathways associated with analgesia while limiting activity in downstream signaling pathways that lead to ORAEs. Differential signaling may fulfill an unmet need in the management of postoperative pain.
Learn More >Methylglyoxal (MGO), an endogenous reactive carbonyl compound, plays a key role in the pathogenesis of diabetic neuropathy. The aim of this study is to investigate the role of MGO in diabetic itch and hypoalgesia, two common symptoms associated with diabetic neuropathy. : Scratching behavior, mechanical itch (alloknesis), and thermal hypoalgesia were quantified after intradermal (i.d.) injection of MGO in naïve mice or in diabetic mice induced by intraperitoneal (i.p.) injection of streptozotocin (STZ). Behavioral testing, patch-clamp recording, transgenic mice, and gene expression analysis were used to investigate the mechanisms underlying diabetic itch and hypoalgesia in mice. : I.d. injection of MGO evoked dose-dependent scratching in normal mice. Addition of MGO directly activated transient receptor potential ankyrin 1 (TRPA1) to induce inward currents and calcium influx in dorsal root ganglia (DRG) neurons or in TRPA1-expressing HEK293 cells. Mechanical itch, but not spontaneous itch was developed in STZ-induced diabetic mice. Genetic ablation of ( ), pharmacological blockade of TRPA1 and Na1.7, antioxidants, and mitogen-activated protein kinase kinase enzyme (MEK) inhibitor U0126 abrogated itch induced by MGO or in STZ-induced diabetic mice. Thermal hypoalgesia was induced by intrathecal (i.t.) injection of MGO or in STZ-induced diabetic mice, which was abolished by MGO scavengers, intrathecal injection of TRPA1 blockers, and in mice. : This study revealed that Na1.7 and MGO-mediated activation of TRPA1 play key roles in itch and hypoalgesia in a murine model of type 1 diabetes. Thereby, we provide a novel potential therapeutic strategy for the treatment of itch and hypoalgesia induced by diabetic neuropathy.
Learn More >Chronic widespread pain (CWP) is one of the most difficult pain conditions to treat due to an unknown etiology and a lack of innovative treatment design and effectiveness. Based upon preliminary findings within the fields of motivational psychology, integrative neuroscience, diaphragmatic breathing, and vagal nerve stimulation, we propose a new treatment intervention, motivational non-directive (ND) resonance breathing, as a means of reducing pain and suffering in patients with CWP. Motivational ND resonance breathing provides patients with a noninvasive means of potentially modulating five psychophysiological mechanisms imperative for endogenously treating pain and increasing overall quality of life.
Learn More >It has been generally thought that activation and sensitization of the trigeminovascular system may contribute to the pathogenesis of migraine. Nevertheless, there is little evidence on abnormalities in peripheral trigeminal afferent nerves from humans in vivo. Alterations of corneal nerves from the ophthalmic branch of the trigeminal nerve may support the notion that trigeminal afferent nerves are involved in migraine pathophysiology. The aim of the present study was to investigate the structural changes in corneal subbasal nerve plexus in patients with episodic migraine (EM) with in vivo confocal microscope (IVCM). In this cross-sectional observational study, 10 EM patients and 10 age- and sex-matched healthy controls were included. Analysis of IVCM images with Image J software was performed to quantify the changes in the corneal subbasal nerve plexus. EM patients showed an increase in nerve fiber length (25.0±2.65 vs 22.3±2.41 mm/mm, =0.047) and nerve fiber density (36.3±7.29 vs 30.5±6.19 fibers/mm, =0.104) as compared with normal controls, but this difference was not statistically significant. Nerve branching and tortuosity were significantly increased in the EM subjects compared to the normal subjects (91.3±13.8 vs 75.0±14.2 branches/mm, =0.030 and 2.30±0.46 versus 1.63±0.52, =0.011, respectively). In addition, nerve sprouts and increased number of Langerhans cells were observed in the EM patients. The morphologic changes of corneal subbasal nerve plexus and Langerhans cell aggregation suggest the presence of nerve regeneration and inflammation in EM. Furthermore, the alterations of corneal nerves from the ophthalmic branch of the trigeminal nerve offer support for the hypothesis that the peripheral trigeminal system may be involved in the pathogenesis of migraine.
Learn More >Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans.
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