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The role of urea in neuronal degeneration and sensitization: an in vitro model of uremic neuropathy.
Background Uremic neuropathy commonly affects patients with chronic kidney disease (CKD), with painful sensations in the feet, followed by numbness and weakness in the legs and hands. The symptoms usually resolve following kidney transplantation, but the mechanisms of uremic neuropathy and associated pain symptoms remain unknown. As blood urea levels are elevated in patients with CKD, we examined the morphological and functional effects of clinically observed levels of urea on sensory neurons. Methods Rat DRG neurons were treated with 10 or 50 mMol/L urea for 48 hours, fixed and immunostained for PGP9.5 and βIII tubulin immunofluorescence, ,. Neurons were also immunostained for TRPV1, TRPM8 and Gap43 expression, and the capsaicin sensitivity of urea or vehicle treated neurons was determined. Results Urea treated neurons had degenerating neurites with diminished PGP9.5 immunofluorescence, and swollen, retracted growth cones. βIII tubulinappeared clumped after urea treatment. Neurite lengths were significantly reduced to 60 ± 2.6 % (10 mMol/L, **P<0.01), and to 56.2 ± 3.3 %, (50 mMol/L, **P<0.01), urea treatment for 48 hours, compared with control neurons. Fewer neurons survived urea treatment, with 70.08 ± 13.3% remaining after10 mMol/L (*P<0.05), and 61.49 ± 7.4 % after 50 mMol/L urea treatment (**P<0.01), compared with controls. The proportion of neurons expressing TRPV1 was reduced after urea treatment, but not TRPM8 expressing neurons. In functional studies, treatment with urea resulted in dose-dependent neuronal sensitization. Capsaicin responses were significantly increased to 115.29 ± 3.4 % (10 mMol/L, **P<0.01) and 125.3 ± 4.2% (50 mMol/L, **P<0.01), compared with controls. Sensitization due to urea was eliminated in the presence of the TRPV1 inhibitor SB705498, the MEK inhibitor PD98059, the PI3 kinase inhibitor LY294002, and the TRPM8 inhibitor AMTB. Conclusion Neurite degeneration and sensitization are consistent with uremic neuropathy, , and provide a disease-relevant model to test new treatments.
Learn More >Orofacial pain is characterized by its easy spread to adjacent areas, thus presenting with primary hyperalgesia (hypersensitivity at the site of injury) and secondary hyperalgesia (extra-territorial hypersensitivity outside the injured zone). However, the mechanisms behind the secondary hyperalgesia are poorly understood. In the present study, we used a mouse model of partial transection of the infraorbital nerve (pT-ION) to study whether calcium channel subunit α2δ1 (Cavα2δ1) and its downstream signaling contributes to the development of secondary hyperalgesia in the orofacial area. pT-ION caused primary (V2 skin) and secondary (V3 skin) hyperalgesia, which was reversed by the Cavα2δ1 antagonist gabapentin and by the expression of Cavα2δ1-targeting interfering RNA in trigeminal ganglion (TG)-V3 neurons. pT-ION induced increased expression of PKC and TRPA1, which was reversed by Cavα2δ1-targeting interfering RNA, and PKC inhibition reversed the upregulation of TRPA1 and gap junction (GJ) proteins induced by pT-ION. Cavα2δ1 overexpression in TG-V2 neurons induced the upregulation of PKC, TRPA1, and the GJ proteins in the TG and trigeminal subnucleus caudalis and induced hypersensitivity in the V3 skin area, which was reversed by TRPA1, GJ, or PKC blockade. Thus, we conclude that Cavα2δ1 contributes to the development of secondary hyperalgesia through its downstream PKC-TRPA1/GJ signaling pathways. Perspective: This study demonstrates that the activation of Cavα2δ1 and the downstream PKC-TRPA1/GJ signaling pathway contributes greatly to trigeminal nerve injury-induced secondary mechanical and cold hyperalgesia. This suggests that inhibitors of Cavα2δ1, TRPA1, or GJs might be effective treatments for nerve injury-induced spreading of orofacial pain.
Learn More >An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.
Learn More >Previous studies have documented that racial minorities and women receive poorer pain care than their demographic counterparts. Providers contribute to these disparities when their pain-related decision-making systematically varies across patient groups. Less is known about racial and gender disparities in children with pain or the extent to which providers contribute to these disparities. In a sample of 129 medical students (henceforth referred to as 'providers'), Virtual Human methodology and a pain-related version of the Implicit Association Test (IAT) were used to examine the effects of patient race/gender on providers' pain assessment/treatment decisions for pediatric chronic abdominal pain, as well as the moderating role of provider implicit pain-related race/gender attitudes. Findings indicated that providers rated Black patients as more distressed (mean difference [MD]=2.33, p<.01, SE=.71, 95% CI=.92, 3.73) and as experiencing more pain-related interference (MD=3.14, p<.01, SE=.76, 95% CI=1.63, 4.64) compared to White patients. Providers were more likely to recommend opioids for Black patients than White patients (MD=2.41, p<.01, SE=.58, 95% CI=1.05, 3.76). Female patients were perceived to be more distressed by their pain (MD=2.14, p<.01, SE=.79, 95% CI=.58, 3.70) than male patients, however there were no gender differences in treatment recommendations. IAT results indicated that providers held implicit attitudes that Black Americans (M=.19, SD=.29) and males (M=.38, SD=.29) were more pain-tolerant than their demographic counterparts; however, these implicit attitudes did not significantly moderate their pain assessment/treatment decisions. Future studies are needed to elucidate specific paths through which the pain experience and care of children differ across racial and gender groups. PERSPECTIVE: Providers' pain assessment (i.e., pain distress/pain interference) and treatment (i.e., opioids) of pediatric pain differs across patient race and to a lesser extent, patient gender. This study represents a critical step in research on pain-related disparities in pediatric pain.
Learn More >Synovitis contributes to temporomandibular joint（TMJ）pain, nevertheless, the detailed nociceptive mechanism remains unclear. In this study, a rat model of TMJ synovitis was induced by intra-articular injection with complete Freund's adjuvant (CFA). After CFA-induced synovitis, pain behaviors were observed. Then, TMJ, trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) tissues were collected, and immunohistochemistry (IHC) was used to detect the expression of substance P (SP) and protein gene product 9.5 (PGP9.5) in the synovium tissue. Furthermore, the gene expression level of SP and PGP9.5 in synovium were detected by reverse transcription-polymerase chain reaction (RT-PCR). Afterwards, the expression of SP in the TG and TNC and c-fos in the TNC was detected by IHC. Compared with the control group, the expression of SP and PGP9.5 nerve fibers density and gene levels of them in the synovium tissue were significantly increased in CFA-induced TMJ synovitis rats. Similarly, SP expression in the TG and TNC, and c-fos expression in the TNC were also obviously increased in CFA-induced TMJ synovitis rats. Collectively, CFA-induced rat TMJ synovitis resulted in obvious pain. This nociceptive reaction could be attributed to the augmented quantity of SP and PGP9.5 positive-stained nerve fibers distributed in the inflammatory synovium, as well as enhanced SP expression in the TG and TNC tissue. C-fos expression in the rat TNC illustrates CFA-induced TMJ synovitis can evoke the acute pain.
Learn More >The neural mechanisms responsible for the initiation and expression of migraines remain unknown. Though there is growing evidence of changes in brainstem anatomy and function between attacks, very little is known about brainstem function and structure in the period immediately prior to a migraine. The aim of this investigation is to use brainstem-specific analyses of diffusion weighted images to determine if the brainstem pain processing regions display altered structure in individuals with migraine across the migraine cycle, and in particular immediately prior to a migraine. Diffusion tensor images (29 controls, 36 migraineurs) were used to assess brainstem anatomy in migraineurs compared with controls. We found that during the interictal phase, migraineurs displayed greater mean diffusivity in the region of the spinal trigeminal nucleus, dorsomedial/dorsolateral pons and midbrain periaqueductal gray matter/cuneiform nucleus. Remarkably, the mean diffusivity returned to controls levels during the 24-hour period immediately prior to a migraine, only to increase again within the three following days. Additionally, fractional anisotropy was significantly elevated in the region of the medial lemniscus/ventral trigeminal thalamic tract in migraineurs compared with controls over the entire migraine cycle. These data show that regional brainstem anatomy changes over the migraine cycle, with specific anatomical changes occurring in the 24 hours prior to onset. These changes may contribute to the activation of the ascending trigeminal pathway by either an increase in basal traffic or by sensitising the trigeminal nuclei to external triggers, with activation ultimately resulting in perception of head pain during a migraine attack. It has been hypothesised that modulation of brainstem pain pathways may be critical for the initiation of migraine attacks. There is some evidence that altered brainstem function, possibly involving increased astrocyte activation, occurs immediately prior to a migraine attack. We sought to obtain evidence to support this theory. Using diffusion tensor imaging, we found that immediately prior to a migraine, mean diffusivity decreased in the spinal trigeminal nucleus, dorsomedial/dorsolateral pons and midbrain periaqueductal gray matter/nucleus cuneiform. Mean diffusivity then increased again immediately following the migraine attack. Decreased mean diffusivity before a migraine is consistent with increased astrocyte activation, since astrocyte processes enlarge during activation. These changes may underlie changes in brainstem function that are essential for the generation of a migraine.
Learn More >Chronic neck pain is a highly prevalent condition, affecting 10% to 24% of the general population. Transcutaneous electrical nerve stimulation (TENS) is the noninvasive, transcutaneous use of electrical stimulation to produce analgesia. It is a simple, low-cost and safe intervention used in clinical practice as an adjunct treatment for painful musculoskeletal conditions that have a considerable impact on daily activities, such as chronic neck pain. This review is a split from a Cochrane Review on electrotherapy for neck pain, published in 2013, and focuses specifically on TENS for chronic neck pain.
Learn More >Opioid prescription in the treatment of chronic pain is frequent and carries a risk of increased morbidity and mortality in a clinically significant number of patients, particularly those who are using opioids in a hazardous manner. Few treatment options are available that target both pain-related interference and hazardous opioid use among patients with chronic pain. In military Veterans, this issue is of particular importance as numerous reports indicate continued high rates of opioid prescription for chronic pain, as well as significant opioid-related problems. The overall aim of the present study was to determine the feasibility of an integrated psychosocial treatment in Veterans with chronic pain, who also have evidence of hazardous opioid use. To examine this aim, a random design was used to assess the feasibility and initial efficacy of integrating two empirically supported interventions: Acceptance and Commitment Therapy for chronic pain and Mindfulness Based Relapse Prevention for opioid misuse. Half of participants were randomized to the integrated treatment group and all participants received usual care (UC) through a Veteran's Administration co-occurring disorders medical clinic to treat chronic pain and opioid misuse. In total, 37 participants were randomized and included in intent to treat (ITT) analyses and 32 individuals were included in per protocol (PP) analyses with 6-month follow-up serving as the primary study endpoint. Feasibility indicators included recruitment, retention, and treatment completion rates. Recruitment fell short of targeted enrollment, although retention and completion were excellent. Primary outcome measures were opioid misuse, pain interference, and pain behavior. Simultaneous multiple regression analyses controlled for pain duration, baseline opioid dose, and baseline value for outcome measures. Results of both the ITT and PP indicated a significant effect in favor of the integrated intervention for opioid misuse, pain interference, and pain behavior. Results support the feasibility of providing an integrated treatment for both opioid risk and pain interference. PERSPECTIVE: Opioid misuse occurs in some opioid-prescribed individuals with chronic pain. Few treatment options exist that target both pain interference and opioid misuse. This study examined feasibility and initial efficacy of an integrated behavioral treatment for Veterans. Feasibility was supported, except recruitment. Efficacy was supported compared to usual care.
Learn More >Psychological factors such as adverse childhood experiences, traumatic life events, interpersonal conflicts and psychological distress play an important role in the predisposition, onset and severity of chronic widespread pain (CWP) and fibromyalgia syndrome (FMS). Therefore, psychological therapies might have the potential to reduce disability as well as symptom and economic burden in patients with CWP and FMS. Recent interdisciplinary guidelines have suggested different strengths of recommendation for psychological therapies for FMS. The aims of this narrative review are to summarise: • Mechanisms of actions. • Evidence on efficacy, tolerability and safety. • Knowledge gaps and needs for future research of psychological therapies for CWP and FMS for non-mental health professionals.
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