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Chronic pain is a significant symptom in patients with autoimmune encephalomyelitis, such as multiple sclerosis and neuromyelitis optica. The most commonly used animal model of these diseases is experimental autoimmune encephalomyelitis (EAE). We previously reported that evoked pain, such as mechanical allodynia, was improved by an anti-IL-6 receptor antibody in EAE mice. However, few reports have evaluated spontaneous pain in EAE mice. Here, we assessed spontaneous pain in EAE mice by utilizing the Mouse Grimace Scale (MGS, a standardized murine facial expression-based coding system) and evaluated the influence of an anti-IL-6 receptor antibody (MR16-1). EAE was induced in female C57BL/6J mice by subcutaneous immunization with myelin oligodendrocyte glycoprotein 35-55 emulsified in adjuvant and administration of pertussis toxin. Mice were placed individually in cubicles and filmed for about 10 min. Ten clear head shots per mouse from the video recording were given a score of 0, 1, or 2 for each of three facial action units: orbital tightening, nose bulge, and ear position. Clinical symptoms of EAE were also scored. Measurement of 5-HT in the spinal cord and functional imaging of the periaqueductal gray (PAG) were also performed. Compared with control mice, MGS score was significantly higher in EAE mice. MR16-1 prevented this increase, especially in pre-onset EAE mice. Promotion of spinal 5-HT turnover and reduction of PAG activity were observed in pre-onset EAE mice. These results suggest that MR16-1 prevented spontaneous pain developed before EAE onset.
Learn More >Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. The present work was addressed to determine whether MR309 might exert preventive effects on CNP development by repeated administration during the first week after SCI in mice. To this end, the MR309 (16 or 32 mg/kg i.p.) modulation on both thermal hyperalgesia and mechanical allodynia development were evaluated weekly up to 28 days post-injury. In addition, changes in pro-inflammatory cytokine (TNF-α, IL-1β) expression and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-α and IL-1β), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development.
Learn More >Informing patients about potential adverse events as part of the informed consent may facilitate the development of nocebo-driven drug adverse events (nocebo side effects). To investigate whether informing about the nocebo effect using a short information sheet can reduce nocebo side effects. A total of = 44 participants with weekly headaches for at least 6 months were recruited using the cover story of a clinical trial for a headache medicine. In reality, all participants took a placebo pill and were randomized to the nocebo information group or the standard leaflet group. Participants were instructed to read the bogus medication leaflet entailing side effects information shortly before pill intake. The nocebo group additionally received an explanation about the nocebo effect as part of the leaflet. Questionnaires were completed at baseline, 2 min, and 4 days after the pill intake. We conducted general linear models with bootstrap sampling. Baseline symptoms were included as a covariate. Most participants (70.5%) reported nocebo side effects at 2 min. Participants who received the nocebo information ( = 24) reported less nocebo symptoms than the control group ( = 20) (estimated difference: 3.3, BCa 95% CI [1.14; 5.15], = 0.01, Cohen's = 0.59). Baseline symptoms, perceived sensitivity to medicine, and side effect expectations each moderated the group effect (estimated difference in slope: 0.47, BCa 95% CI [0.19; 0.73], = 0.001, = 0.75; 1.07 [0.27; 1.61], = 0.006, = 0.73; 1.57 [0.38; 2.76], = 0.02, = 0.58). No group differences were found at 4-day follow-up. After revealing the actual aim of the study, 86% of the participants evaluated the nocebo information to be helpful in general. Results provide the first evidence that informing about the nocebo effect can reduce nocebo side effects.
Learn More >Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.
Learn More >Recently, the role of CXCR2 in nociception has been noted. Our studies provide new evidence that the intrathecal administration of its CINC ligands (Cytokine-Induced Neutrophil Chemoattractant; CXCL1-3) induces pain-like behavior in naïve mice, and the effect occurring shortly after administration is associated with the neural location of CXCR2, as confirmed by immunofluorescence. RT-qPCR analysis showed, for the first time, raised levels of spinal CXCR2 after chronic constriction injury (CCI) of the sciatic nerve in rats. Originally, on day 2, we detected escalated levels of the spinal mRNA of all CINCs associated with enhancement of the protein level of CXCL3 lasting until day 7. Intrathecal administration of CXCL3 neutralizing antibody diminished neuropathic pain on day 7 after CCI. Interestingly, CXCL3 is produced in lipopolysaccharide-stimulated microglial, but not astroglial, primary cell cultures. We present the first evidence that chronic intrathecal administrations of the selective CXCR2 antagonist, NVP CXCR2 20, attenuate neuropathic pain symptoms and CXCL3 expression after CCI. Moreover, in naïve mice, this antagonist prevented CXCL3-induced hypersensitivity. However, NVP CXCR2 20 did not diminish glial activation, thus not enhancing morphine/buprenorphine analgesia. These results provide novel insight into the crucial role of CXCR2 in neuropathy based on CXCL3 modulation, which may become a potential therapeutic target in pain treatment.
Learn More >Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.
Learn More >Microglial cells in the central nervous system (CNS) are crucial in maintaining a healthy environment for neurons to function properly. However, aberrant microglial cell activation can lead to excessive generation of neurotoxic proinflammatory mediators and neuroinflammation, which represents a contributing factor in a wide spectrum of CNS pathologies, including ischemic stroke, traumatic brain damage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, psychiatric disorders, autism spectrum disorders, and chronic neuropathic pain. Oxidative stress is a salient and common feature of these conditions and has been strongly implicated in microglial cell activation and neuroinflammation. The transient receptor potential melastatin-related 2 (TRPM2) channel, an oxidative stress-sensitive calcium-permeable cationic channel, is highly expressed in microglial cells. In this review, we examine the recent studies that provide evidence to support an important role for the TRPM2 channel, particularly TRPM2-mediated Ca signaling, in mediating microglial cell activation, generation of proinflammatory mediators and neuroinflammation, which are of relevance to CNS pathologies. These findings lead to a growing interest in the TRPM2 channel, a new player in neuroinflammation, as a novel therapeutic target for CNS diseases.
Learn More >A number of studies have been published proposing various approaches to the treatment of neuropathic pain; however, to our knowledge, no attempts have been made to compare gabapentin and fentanyl in patients with lumbar radiculopathy. We evaluated the relative efficacy and safety of fentanyl matrix and gabapentin for the treatment of chronic neuropathic pain of radicular origin. The study was designed as a randomized blind multicentered parallel-group noninferiority trial. A total of 108 patients with moderate-to-severe pain (≥4 intensity on an 11-point numeric rating scale) were randomly prescribed either fentanyl matrix or gabapentin over a period of 56 days. In the primary analysis, the noninferiority of fentanyl matrix treatment was evaluated in relation to the efficacy of gabapentin based on the pain intensity difference (PID) at 56 days after the first dose of the drugs. Secondary endpoints included pain relief, improvement in functional status (the Korean-Oswestry Disability Index (K-ODI)), improvement in depressive symptoms (Korean-Beck Depression Index (K-BDI)) between the 28th and 56th day, and adverse events (AEs). Analysis of the primary efficacy endpoint established the noninferiority of fentanyl matrix compared with gabapentin, with no statistically significant difference observed in the PID after 56 days for the two treatment groups. Similarly, analysis of pain relief revealed no significant differences between the groups on days 28 and 56. There was no difference in the K-ODI and K-BDI between the groups during the study period. The overall incidence of at least one AE was similar for fentanyl matrix (67.3%) and gabapentin (69.6%). The most commonly reported AEs for patients treated with fentanyl matrix and gabapentin included dizziness (30.8% vs. 44.6%, respectively), somnolence (26.9% vs. 35.7%), and constipation (15.4% vs. 17.9%). This study demonstrated that the analgesic effect of fentanyl matrix is noninferior in comparison with gabapentin and supports the use of fentanyl matrix as an effective and safe treatment for moderate-to-severe chronic neuropathic pain. This trial is registered with NCT01127100.
Learn More >Chronic migraine (CM) is the most disabling form of migraine, because pharmacological treatments have low efficacy and cumbersome side effects. New evidence has shown that migraine is primarily a disorder of brain plasticity and migraine chronification depends on a maladaptive process favoring the development of a brain state of hyperexcitability. Due to the ability to induce plastic changes in the brain, researchers started to look at Non-Invasive Brain Stimulation (NIBS) as a possible therapeutic option in migraine field. On one side, NIBS techniques induce changes of neural plasticity that outlast the period of the stimulation (a fundamental prerequisite of a prophylactic migraine treatment, concurrently they allow targeting neurophysiological abnormalities that contribute to the transition from episodic to CM. The action may thus influence not only the cortex but also brainstem and diencephalic structures. Plus, NIBS is not burdened by serious medication side effects and drug-drug interactions. Although the majority of the studies reported somewhat beneficial effects in migraine patients, no standard intervention has been defined. This may be due to methodological differences regarding the used techniques (e.g., transcranial magnetic stimulation, transcranial direct current stimulation), the brain regions chosen as targets, and the stimulation types (e.g., the use of inhibitory and excitatory stimulations on the basis of opposite rationales), and an intrinsic variability of stimulation effect. Hence, it is difficult to draw a conclusion on the real effect of neuromodulation in migraine. In this article, we first will review the definition and mechanisms of brain plasticity, some neurophysiological hallmarks of migraine, and migraine chronification-related (dys)plasticity. Secondly, we will review available results from therapeutic and physiological studies using neuromodulation in CM. Lastly we will discuss the results obtained in these preventive trials in the light of a possible effect on brain plasticity.
Learn More >Regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. This therapy's intention is to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of underperforming conventional therapy midst the hopes and high expectations of patients and medical personnel alike. But, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public presentation and promises as well as in its use.
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