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Entrapment neuropathies such as carpal tunnel syndrome, radiculopathies, or radicular pain are the most common peripheral neuropathies and also the most common cause for neuropathic pain. Despite their high prevalence, they often remain challenging to diagnose and manage in a clinical setting. Summarising the evidence from both preclinical and clinical studies, this review provides an update on the aetiology and pathophysiology of entrapment neuropathies. Potential mechanisms are put in perspective with clinical findings. The contemporary assessment is discussed and diagnostic pitfalls highlighted. The evidence for the noninvasive and surgical management of common entrapment neuropathies is summarised and future areas of research are identified.
Learn More >Chronic pain and depression often co-occur. The mechanisms underlying this comorbidity are incompletely understood. Here, we investigated the role of CD3 T cells in an inflammatory model of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in mice.
Learn More >The role of brain-derived neurotrophic factor (BDNF) signaling in chronic pain has been well documented. Given the important central role of BDNF in long term plasticity and memory, we sought to engineer a high affinity, peripherally-restricted monoclonal antibody against BDNF to modulate pain. BDNF shares 100% sequence homology across human and rodents; thus, we selected chickens as an alternative immune host for initial antibody generation. Here, we describe the affinity optimization of complementarity-determining region-grafted, chicken-derived R3bH01, an anti-BDNF antibody specifically blocking the TrkB receptor interaction. Antibody optimization led to the identification of B30, which has a > 300-fold improvement in affinity based on BIAcore, an 800-fold improvement in potency in a cell-based pERK assay and demonstrates exquisite selectivity over related neurotrophins. Affinity improvements measured translated to pharmacological activity, with B30 demonstrating a 30-fold improvement in potency over parental R3bH01 in a peripheral nerve injury model. We further demonstrate that peripheral BDNF plays a role in maintaining the plasticity of sensory neurons following nerve damage, with B30 reversing neuron hyperexcitability associated with heat and mechanical stimuli in a dose-dependent fashion. In summary, our data demonstrate that effective sequestration of BDNF via a high affinity neutralizing antibody has potential utility in modulating the pathophysiological mechanisms that drive chronic pain states.
Learn More >The human gut microbiome constitutes a diverse and dynamic community of microorganisms that inhabit the digestive tract. In recent years, there is growing appreciation for the role of the gut microbiome in host health and disease. Gut bacteria are involved in the pathogenesis of numerous medical conditions in a variety of medical fields including gastroenterology, metabolic, rheumatologic, neurologic and psychiatric disorders. Recently, evidence is mounting that gut bacteria could also play a role in chronic pain and specifically fibromyalgia (FM). The composition of the gut bacterial community is altered in individuals with FM, with an altered abundance of a small subset of bacterial species. Some of these species, either with increased or decreased abundance in patients, have established metabolic activity which could have pertinence in the expression of FM symptoms. The putative mechanisms which could allow these bacterial species to affect pain, fatigue, mood and other symptoms include the entry of short-chain-fatty-acids, bile acids, neurotransmitters and bacterial antigens into the host circulation. While these are merely the first steps in understanding the role of the gut microbiome in chronic pain and specifically FM, one might envision exciting future perspectives for better mechanistic understanding of FM, for the development of objective diagnostic aids and potentially for new therapeutic modalities.
Learn More >Recent studies indicate that presynaptic long-term potentiation (pre-LTP) in the anterior cingulate cortex (ACC) may contribute to chronic pain-related anxiety. In addition to the ACC, the insular cortex (IC) has also been indicated in chronic pain and its related emotional disorders. In the present study, we used a 64-channel multielectrode dish (MED64) system to record pre-LTP in the IC. We showed that low-frequency stimulation paired with a GluK1-containing kainate receptor agonist induced NMDA receptor-independent pre-LTP in the IC of wide-type (WT) mice. This form of pre-LTP was blocked in the IC of adenylyl cyclase subtype 1 (AC1) KO mice. Furthermore, a selective AC1 inhibitor NB001 blocked pre-LTP in the IC with a dose-dependent manner. Taken together, our results suggest that AC1 contributes to pre-LTP in the IC of adult mice and NB001 may produce anxiolytic effects by inhibiting pre-LTP in the ACC and IC.
Learn More >Migraine is the seventh most disabling disorder globally, with prevalence of 11.7% worldwide. One of the prevailing mechanisms is the activation of the trigeminovascular system, and calcitonin gene-related peptide (CGRP) is an important therapeutic target for migraine in this system. Recent studies suggested an emerging role of pituitary adenylate cyclase-activating peptide (PACAP) in migraine. However, the relation between CGRP and PACAP and the role of PACAP in migraine remain undefined. In this study, we established a novel repetitive (one, three, and seven days) electrical stimulation model by stimulating dura mater in conscious rats. Then, we determined expression patterns in the trigeminal ganglion and the trigeminal nucleus caudalis of the trigeminovascular system. Electrical stimulation decreased facial mechanical thresholds, and the order of sensitivity was as follows: vibrissal pad >inner canthus >outer canthus (P < 0.001). The electrical stimulation group exhibited head-turning and head-flicks (P < 0.05) nociceptive behaviors. Importantly, electrical stimulation increased the expressions of CGRP, PACAP, and the PACAP-preferring type 1 (PAC1) receptor in both trigeminal ganglion and trigeminal nucleus caudalis (P < 0.05). The expressions of two vasoactive intestinal peptide (VIP)-shared type 2 (VPAC1 and VPAC2) receptors were increased in the trigeminal ganglion, whereas in the trigeminal nucleus caudalis, their increases were peaked on Day 3 and then decreased by Day 7. PACAP was colocalized with NEUronal Nuclei (NeuN), PAC1, and CGRP in both trigeminal ganglion and the trigeminal nucleus caudalis. Our results demonstrate that the repetitive electrical stimulation model can simulate the allodynia during the migraine chronification, and PACAP plays a role in the pathogenesis of migraine potentially via PAC1 receptor.
Learn More >The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception related prefrontal anterior cingulate cortex (ACC). However, less information is available for the functional roles of CGRP in cortical regions such as the ACC. Recent studies have consistently demonstrated that long-term potentiation (LTP) is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP8-37 blocked CGRP-induced chemical LTP and the recruitment of inactive channels. CGRP-induced LTP was also blocked by NMDA receptor antagonist AP-5. Consistently, application of CGRP increased NMDA receptor mediated excitatory postsynaptic currents (EPSCs). Finally, we found that CGRP-induced LTP requires activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and PKA. Genetic deletion of AC1 using AC1-/- mice, an AC1 inhibitor NB001 or a PKA inhibitor KT5720 all reduced or blocked CGRP induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.
Learn More >Features suggestive of neuropathic pain (NP) have been described in RA in addition to nociceptive pain. We aimed to determine the clinical predictors of NP in RA patients and study its association with radiographic structural damage.
Learn More >Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of many tumors. However, a main side-effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to changes in chemotherapeutic treatment. Although symptoms associated with CIPN are recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia (DRG) following vincristine, oxaliplatin, and cisplatin treatment with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq revealed 368, 295 and 256 differential expressed genes (DEGs) induced by treatment with vincristine, oxaliplatin and cisplatin, respectively and only five shared genes were dysregulated in all three groups. Cell type enrichment analysis and gene set enrichment analysis showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. Perspective: These results provide insight into the recruitment of immune responses to DRG and indicate enhanced neuro-inflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.
Learn More >Patients with cancer, especially breast, prostate, and lung cancer, commonly experience bone metastases that are difficult to manage and are associated with bone cancer pain (BCP). Amitriptyline is often used to treat chronic pain, such as neuropathic pain. In the present study, the effects of amitriptyline on the mechanical withdrawal threshold (MWT) and its underlying mechanisms were evaluated in rat models of BCP. Walker 256 rat mammary gland carcinoma cells were injected into the bone marrow cavity of the right tibia of rats to provoke BCP. Then, amitriptyline was intraperitoneally administered twice daily from fifth day after the operation. Rats with bone cancer showed an apparent decline in the MWT at day 11 after Walker 256 cells inoculation. The levels of the glutamate transporter GLAST in the spinal cord dorsal horn decreased remarkably, and the concentration of the excitatory amino acid (EAA) glutamate (Glu) in the cerebrospinal fluid (CSF) increased substantially. Amitriptyline injection could prevent the decline of MWT in BCP rats. In addition, GLAST was upregulated on the glial cell surface, and Glu levels were reduced in the CSF. However, amitriptyline injection could not prevent the BCP-induced reduction in GLAST in the glial cell cytosol, it further downregulated cytosolic GLAST. Amitriptyline had no significant effect on GLAST mRNA expression, and BCP-invoked PKA/PKC upregulation was prevented. Taken together, these results suggest that the intraperitoneal injection of amitriptyline can prevent the decrease of MWT in BCP rats, the underlying mechanisms may be associated with the inhibition of PKA/PKC expression, thus promoting GLAST trafficking onto the glial cell surface and reducing EAA concentrations in the CSF.
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