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Pain in response to various types of acute injury can be a protective stimulus to prevent the organism from using the injured part and allow tissue repair and healing. On the other hand, neuropathic pain, defined as 'pain caused by a lesion or disease of the somatosensory nervous system', is a debilitating pathology. The TRPA1 neurons in the Dorsal Root Ganglion (DRG) respond to reactive oxygen species (ROS) and induce pain. In acute nerve injury and inflammation, macrophages infiltrating the site of injury undergo an oxidative burst, and generate ROS that promote tissue repair and induce pain via TRPA1. The latter discourages using the injured limb, with a lack of movement helping wound healing. In chronic inflammation caused by diabetes, cancer etc., ROS levels increase systemically and modulate TRPA1 neuronal functions and cause debilitating neuropathic pain. It is important to distinguish between drug targets that elicit protective vs. debilitating pain when developing effective drugs for neuropathic pain. In this context, the connection of the Angiotensin type 2 receptor (ATR) to neuropathic pain presents an interesting dilemma. Several lines of evidence show that ATR activation promotes anti-inflammatory and anti-nociceptive signaling, tissue repair, and suppresses ROS in chronic inflammatory models. Conversely, some studies suggest that ATR antagonists are anti-nociceptive and therefore ATR is a drug target for neuropathic pain. However, ATR expression in nociceptive neurons is lacking, indicating that neuronal ATR is not involved in neuropathic pain. It is also important to consider that Novartis terminated their phase II clinical trial (EMPHENE) to validate that ATR antagonist EMA401 mitigates post-herpetic neuralgia. This trial, conducted in Australia, United Kingdom, and a number of European and Asian countries in 2019, was discontinued due to pre-clinical drug toxicity data. Moreover, early data from the trial did not show statistically significant positive outcomes. These facts suggest that may ATR not be the proper drug target for neuropathic pain in humans and its inhibition can be harmful.
Our previous studies implicated glycosylation of the Ca3.2 isoform of T-type Ca channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant Ca3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our study we used whole-cell recordings of current-voltage relationships to confirm that Ca3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and Ca3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the Ca3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native Ca3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in Ca3.2 channels directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.
Spinal manipulative therapy (SMT) helps to reduce chronic low back pain (cLBP). However, the underlying mechanism of pain relief and the neurological response to SMT remains unclear. We utilized brain functional magnetic resonance imaging (fMRI) upon the application of a real-time spot pressure mechanical stimulus to assess the effects of SMT on patients with cLBP. Patients with cLBP (Group 1, = 14) and age-matched healthy controls without cLBP (Group 2, = 20) were prospectively enrolled. Brain fMRI was performed for Group 1 at three time points: before SMT (TP1), after the first SMT session (TP2), and after the sixth SMT session (TP3). The healthy controls (Group 2) did not receive SMT and underwent only one fMRI scan. During fMRI scanning, a real-time spot pressure mechanical stimulus was applied to the low back area of all participants. Participants in Group 1 completed clinical questionnaires assessing pain and quality of life using a visual analog scale (VAS) and the Chinese Short Form Oswestry Disability Index (C-SFODI), respectively. Before SMT (TP1), there were no significant differences in brain activity between Group 1 and Group 2. After the first SMT session (TP2), Group 1 showed significantly greater brain activity in the right parahippocampal gyrus, right dorsolateral prefrontal cortex, and left precuneus compared to Group 2 ( < 0.05). After the sixth SMT session (TP3), Group 1 showed significantly greater brain activity in the posterior cingulate gyrus and right inferior frontal gyrus compared to Group 2 ( < 0.05). After both the first and sixth SMT sessions (TP2 and TP3), Group 1 had significantly lower VAS pain scores and C-SFODI scores than at TP1 ( < 0.001). We observed alterations in brain activity in regions of the default mode network in patients with cLBP after SMT. These findings suggest the potential utility of the default mode network as a neuroimaging biomarker for pain management in patients with cLBP. Chinese Clinical Trial Registry, identifier ChiCTR1800015620.
Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.
A national primary and secondary healthcare-level study in the Czech Republic has not yet been conducted to evaluate the prevalence of migraine. We analyzed the current treatment patterns (acute and prophylactic) in migraine patients and the number of migraine patients potentially eligible for treatment with recent calcitonin gene-related peptide (CGRP) pathway-targeted therapies.
Endometriosis is a chronic and debilitating condition affecting ∼10% of women. Endometriosis is characterized by infertility and chronic pelvic pain, yet treatment options remain limited. In many respects this is related to an underlying lack of knowledge of the etiology and mechanisms contributing to endometriosis-induced pain. Whilst many studies focus on retrograde menstruation, and the formation and development of lesions in the pathogenesis of endometriosis, the mechanisms underlying the associated pain remain poorly described. Here we review the recent clinical and experimental evidence of the mechanisms contributing to chronic pain in endometriosis. This includes the roles of inflammation, neurogenic inflammation, neuroangiogenesis, peripheral sensitization and central sensitization. As endometriosis patients are also known to have co-morbidities such as irritable bowel syndrome and overactive bladder syndrome, we highlight how common nerve pathways innervating the colon, bladder and female reproductive tract can contribute to co-morbidity via cross-organ sensitization.
Migraine is a common and highly disabling headache disorder associated with a substantial socioeconomic burden. Migraine treatments can be categorized as preventive treatment, aimed at reducing the frequency and severity of migraine attacks, and acute therapy, intended to abort attacks. Traditionally, acute treatment can be classified as specific (ergot derivatives and triptans) or nonspecific (analgesics and nonsteroidal anti-inflammatory drugs). Triptans, a class of 5-HT receptor agonists with some affinity for the 5-HT receptor subtype, have been proven to be efficacious for acute treatment of moderate to severe migraine and have been deemed the gold standard. The availability of triptans in non-oral formulations, such as subcutaneous (SC) and intranasal forms, can be beneficial for patients who suffer from prominent nausea or vomiting, have a suboptimal response to oral agents, and/or seek a more rapid onset of treatment effects. However, triptans are contraindicated in patients with preexisting cardiovascular and/or cerebrovascular diseases due to their 5-HT-mediated vasoconstrictive action. For this reason, studies have focused on the development of ditans, a group of antimigraine drugs targeting 5-HT and 5-HT receptors. Unfortunately, 5-HT receptor agonists have been shown to be ineffective in the acute treatment of migraine. Several ditans targeting the 5-HT receptor have been developed and have shown no vasoconstrictive effect in preclinical studies, but only two of them, lasmiditan and LY334370, have been tested in clinical trials for migraine, and only lasmiditan has reached to Phase III clinical trials. These Phase III trials have demonstrated the efficacy and safety of lasmiditan, a selective 5-HT receptor agonist, in acute migraine treatment. Lasmiditan might offer an alternative migraine therapy without cardiovascular risks. This review will summarize the development of agents targeting the 5-HT and 5-HT receptors and the clinical evidence supporting the use of these agents for acute migraine treatment.
The life altering nature of major limb amputations may be further complicated by neuroma formation in up to 60% of the estimated 2 million major limb amputees in the United States. This can be a source of pain and functional limitation of the residual limb. Pain associated with neuromas may limit prosthetic limb use, require reoperation, lead to opioid dependence, and dramatically reduce quality of life. A number of management options have been described including excision alone, excision with repair, excision with transposition, and targeted muscle reinnervation. Targeted muscle reinnervation has been shown to reduce phantom limb and neuroma pain for patients with upper and lower extremity amputations. It may be performed at the time of initial amputation to prevent pain development or secondarily for the treatment of established pain. Encouraging outcomes have been reported, and targeted muscle reinnervation is emerging as a leading surgical technique for pain prevention in patients undergoing major limb amputations and pain management in patients with pre-existing amputations.
It has been reported that N-cadherin and cAMP response element binding protein (CREB) in the spinal cord are critical for synaptogenesis and regulation of excitatory synapse function, which could underlie chronic pain development. The aim of the present study was to investigate the role of spinal N-cadherin/CREB signaling in postsurgical pain chronicity following chronic alcohol consumption.