Differential Brain Perfusion Changes Following Two Mind–Body Interventions for Fibromyalgia Patients: an Arterial Spin Labelling fMRI Study

Objectives Further mechanistic insight on mind–body techniques for fibromyalgia (FMS) is needed. Arterial spin labelling (ASL) imaging can capture changes in regional cerebral blood flow (rCBF) that relate to spontaneous pain. Methods We recruited FMS patients undergoing either mindfulness-based stress reduction training (MBSR, n = 14) or a psychoeducational programme (FibroQoL, n = 18), and a control FMS group with no add-on treatment (n = 14). We acquired whole-brain rCBF maps and self-report measures at baseline and following treatment and explored interaction effects in brain perfusion between the treatment group and session with a focus on the amygdala, the insula and the anterior cingulate cortex (ACC). Results We identified a significant interaction effect in the amygdala, which corresponded with rCBF decreases following FibroQoL specifically. At baseline, rCBF in the amygdala for the FibroQoL group correlated with pain catastrophizing and anxiety scores, but not after treatment, suggesting a decoupling between activity in the amygdala and negative emotional symptoms of FMS as a consequence of treatment. Baseline rCBF correlated positively with pain symptoms in the ACC and the anterior insula across all patients; moreover, the correlation between rCBF changes post intervention in the insula and pain improvement was negative for both treatments and significantly different from the control group. We suggest that there is disruption of the typical relationship between clinical pain and activity as a product of these two nonpharmacological therapies. Conclusions We have demonstrated that different mind-to-body treatments correspond to differential changes in clinical symptoms and brain activity patterns, which encourages future research investigating predictors of treatment response. Trial Registration NCT02561416.

Advances With Non-coding RNAs in Neuropathic Pain

Neuropathic pain (NP) is one of the most common types of clinical pain. The common causes of this syndrome include injury to the central or peripheral nervous systems and pathological changes. NP is characterized by spontaneous pain, hyperalgesia, abnormal pain, and paresthesia. Because of its diverse etiology, the pathogenesis of NP has not been fully elucidated and has become one of the most challenging problems in clinical medicine. This kind of pain is extremely resistant to conventional treatment and is accompanied by serious complications. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), contribute to diverse biological processes by regulating the expression of various mRNAs involved in pain-related pathways, at the posttranscriptional level. Abnormal regulation of ncRNAs is closely related to the occurrence and development of NP. In this review, we summarize the current state of understanding of the roles of different ncRNAs in the development of NP. Understanding these mechanisms can help develop novel therapeutic strategies to prevent or treat chronic pain.

A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain

Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.

The Application of Manual Techniques in Masticatory Muscles Relaxation as Adjunctive Therapy in the Treatment of Temporomandibular Joint Disorders

Temporomandibular disorders (TMD) are primarily characterized by pain as well as disorders concerning the proper functioning of individual elements of the stomatognathic system (SS). The aim of the study was to compare the degree of relaxation of the anterior part of the temporal muscles and the masseter muscles, achieved through the use of post-isometric relaxation and myofascial release methods in patients requiring prosthetic treatment due to temporomandibular joint disorders with a dominant muscular component. Sixty patients who met the inclusion criteria were alternately assigned to one of the two study groups, either group I—patients received post-isometric relaxation treatment (PIR), or group II—patients received myofascial release treatment (MR). The series of ten treatments were performed in both groups. The comparative assessment was based on physiotherapeutic examination, a surface electromyography (sEMG) of the anterior temporal and masseter muscles and the intensity of spontaneous masticatory muscle pain, assessed using the Visual Analogue Scale (VAS). We observed a significant decrease in the electrical activity of examined muscles and a significant drop in the intensity of spontaneous pain in the masticatory muscles both in group I and II. There were no significant differences between groups. Both therapeutic methods may be used as successful forms of adjunctive therapy in the prosthetic treatment of TMD. The trial was registered with an international clinical trials register.

IL-23 Enhances C-Fiber-Mediated and Blue Light-Induced Spontaneous Pain in Female Mice

The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. In situ hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 μm2) Trpv1+ neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.

Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients

Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m2 are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody–antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients.

Activation of peripheral neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain

Background. Acute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injury-induced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for peripheral nerve injury-induced pain chronification, questioning its role in the development of pain-induced mood alterations. Methods. In a model of paw incisional pain, mice underwent single (SI) or double incision (DI) and went through behavioral and molecular phenotyping with the evaluation of both sensorial and emotional pain components. The role of FLT3 was then investigated either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations. Results. DI mice showed significant anxiodepressive-like and spontaneous pain behaviors while SI mice did not. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with a potentiation of spinal microglial activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI induced-mechanical hypersensitivity. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a significant microglial activation while FLT3 inhibition blunted the development of persistent pain and depression after DI. Conclusions. Our results show for the first time that the repetition of a peripheral lesion facilitates not only exaggerated nociceptive behaviors but also anxiodepressive disorders. The inhibition of FLT3 could become a promising therapy in the management of pain sensitization and related mood alterations.

Comparative effect of dense-and-disperse versus non-repetitive and non-sequential frequencies in electroacupuncture-induced analgesia in a rodent model of peripheral neuropathic pain

Background: Neuropathic pain (NP) is a complex disease that remains challenging to treat. Low-frequency dense-and-disperse (DD) electroacupuncture (EA) has been used as adjuvant therapy for neuropathic pain; however, its analgesic effect decreases as stimulation time increases, or when it is repeatedly used. We hypothesized that a new frequency parameter could improve the effectiveness of EA, and aimed to compare the efficacy and duration of the analgesic effect between classic DD-EA and non-repetitive and non-sequential frequency (random frequency (RF)-EA) in neuropathic rats. Furthermore, the effect of RF-EA at local traditional acupuncture point locations versus auricular vagus nerve stimulation (aVNS) was evaluated. Methods: Male Wistar rats with peripheral neuropathy were subjected to a single session of DD-EA or RF-EA for 20 or 40 min at ST36 + GB34. An additional group of rats was treated with RF-EA for 20 min using aVNS at the appropriate ear point locations. Paw pressure test, von Frey filaments and spontaneous pain scores were evaluated. Sham-operated rats were used as controls. Results: In all, 20 min of RF-EA reversed hyperalgesia (for 24 h) and allodynia (for 8 h), showing a longer analgesic effect than DD-EA. Both RF-EA and DD-EA induced partial inhibition of spontaneous pain for 8 h. Forty minutes of DD-EA did not interfere with the NP phenomena; however, RF-EA induced significant long-term analgesia. aVNS induced an analgesic effect similar to local stimulation. Conclusion: This pilot study shows that RF-EA at both local traditional acupuncture point and auriculotherapy point locations induces long-lasting analgesia in neuropathic rats, and more effectively so than classical DD-EA.

C/EBPβ Participates in Nerve Trauma-Induced TLR7 Upregulation in Primary Sensory Neurons

Nerve trauma-induced toll-like receptor 7 (TLR7) expression level increase in primary sensory neurons in the damaged dorsal root ganglion (DRG) avails to neuropathic pain, but the reason is still unknown. In the current study, we showed that unilateral lumbar 4 (L4) spinal nerve ligation (SNL) upregulated CCAAT/enhancer-binding protein-β (C/EBPβ) expression in ipsilateral L4 DRG. Preventing this elevation attenuated the SNL-induced upregulation of TLR7 in the ipsilateral L4 DRG and inhibited cold/thermal hyperalgesia and mechanical allodynia. Mimicking nerve trauma-induced C/EBPβ upregulation generated an elevated level of TLR7 in injected DRG, augmented responses to cold/thermal/mechanical stimuli while causing ipsilateral spontaneous pain with no SNL. Mechanistically, SNL upregulated binding of increased C/EBPβ to Tlr7 promoter in ipsilateral L4 DRG. Accorded that C/EBPβ could trigger the activation of Tlr7 promoter and co-expressed with Tlr7 mRNA in individual DRG neurons, our findings strongly suggest the role of C/EBPβ in nerve trauma-mediated TLR7 upregulation in damaged primary sensory neurons.

Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders

Background Neuropathic pain in neuroimmunological disorders refers to pain caused by a lesion or disease of the somatosensory system such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS and NMOSD are autoimmune disorders of the central nervous system, and ≥ 50% of patients with these disorders experience chronic neuropathic pain. The currently available medications for the management of neuropathic pain have limited effectiveness in patients with MS and NMOSD, and there is an unmet medical need to identify novel therapies for the management of chronic neuropathic pain in these patients. In this review article, we summarize the role of interleukin-6 (IL-6) in the pathogenesis of MS and NMOSD and the ameliorative effects of anti–IL-6 therapies in mouse models of experimental autoimmune encephalomyelitis (EAE). Main body Intraperitoneal injection of MR16-1, an anti–IL-6 receptor (IL-6R) antibody, reduced mechanical allodynia and spontaneous pain in EAE mice, which was attributed to a reduction in microglial activation and inhibition of the descending pain inhibitory system. The effect of anti–IL-6 therapies in ameliorating neuropathic pain in the clinical setting is controversial; a reduction in pain intensity has been reported with an anti–IL-6 antibody in four studies, namely a case report, a pilot study, a retrospective observational study, and a case series. Pain intensity was evaluated using a numerical rating scale (NRS), with a lower score indicating lesser pain. A reduction in the NRS score was reported in all four studies. However, in two randomized controlled trials of another anti–IL-6R antibody, the change in the visual analog scale pain score was not statistically significantly different when compared with placebo. This was attributed to the low mean pain score at baseline in both the trials and the concomitant use of medications for pain in one of the trials, which may have masked the effects of the anti–IL-6R antibody on neuropathic pain. Conclusion Thus, anti–IL-6 therapies might have a potential to reduce neuropathic pain, but further investigations are warranted to clarify the effect of inhibition of IL-6 signaling on neuropathic pain associated with MS and NMOSD.