Mechanisms Of Peripheral Neuropathic Pain Research Articles

Peripheral mechanisms of peripheral neuropathic pain.

Peripheral neuropathic pain (PNP), neuropathic pain that arises from a damage or disease affecting the peripheral nervous system, is associated with an extremely large disease burden, and there is an increasing and urgent need for new therapies for treating this disorder. In this review we have highlighted therapeutic targets that may be translated into disease modifying therapies for PNP associated with peripheral neuropathy. We have also discussed how genetic studies and novel technologies, such as optogenetics, chemogenetics and single-cell RNA-sequencing, have been increasingly successful in revealing novel mechanisms underlying PNP. Additionally, consideration of the role of non-neuronal cells and communication between the skin and sensory afferents is presented to highlight the potential use of drug treatment that could be applied topically, bypassing drug side effects. We conclude by discussing the current difficulties to the development of effective new therapies and, most importantly, how we might improve the translation of targets for peripheral neuropathic pain identified from studies in animal models to the clinic.

Antisense oligonucleotides targeting alternative splicing of Nrcam exon 10 suppress neurite outgrowth of ganglion sensory neurons in vitro.

Neuron-glial-related cell adhesion molecule (NrCAM) is a neuronal cell adhesion molecule that has been shown to be involved in several cellular processes in the peripheral nervous system, including neurite outgrowth. We recently reported that alternative splicing of Nrcam mRNA at exon 10 in the dorsal root ganglion (DRG) contributes to the peripheral mechanism of neuropathic pain. Specially, Nrcam antisense oligonucleotides (ASO) targeting Nrcam exon 10, attenuated neuropathic pain hypersensitivities in mice. Here, we investigated the effect of Nrcam ASO on neurite outgrowth of DRG neurons in vitro. By immunostaining DRG neurons with different DRG markers, Nrcam ASO significantly reduced neurite lengths in neurofilament 200-, calcitonin gene-related peptide and isolectin B4-positive neurons in primary DRG neuronal culture. Moreover, Nrcam ASO activates epidermal growth factor receptor, which may mediate the effect of Nrcam ASO on neurite outgrowth of cultured DRG neurons. These results provide evidence that Nrcam ASO suppresses neurite outgrowth in DRG neurons by regulating alternative splicing of Nrcam gene at exon 10 and activation of epidermal growth factor receptor signaling, indicating the differential roles of NrCAM variants/isoforms in neurite outgrowth.

Electro-acupuncture Suppresses AXL Expression in Dorsal Root Ganglion Neurons and Enhances Analgesic Effect of AXL Inhibitor in Spinal Nerve Ligation Induced-Neuropathic Pain Rats.

Electro-acupuncture (EA) has been used for clinic analgesia for many years. However, its mechanisms are not fully understood. We recently reported that AXL, a tyrosine kinase receptor, contributes to the peripheral mechanism of neuropathic pain. We here aim to figure out the significance of EA on neuropathic pain mediated by AXL in dorsal root ganglion (DRG). Spinal nerve ligation (SNL) was used as a neuropathic pain model. EA was applied at ''Huantiao'' (GB-30) and ''Yanglingquan'' (GB-34) acupoints for 30min daily from day 7 to day 10 after SNL. EA not only gradually attenuated SNL-induced mechanical allodynia, but also suppressed the expression of phosphorylated AXL (p-AXL) and AXL in injured DRGs of SNL rats examined by western blotting and immunofluorescence. Moreover, intrathecal injection of the subthreshold dose of AXL inhibitor TP0903, significantly prolonged the analgesic time of single EA treatment and enhanced the analgesic effect of repeated EA treatments, suggesting a synergic effect of EA and AXL inhibitor. These results indicate that AXL signaling underlies EA analgesia and combination of AXL inhibitor and EA might be a new strategy for clinic analgesia on neuropathic pain.

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons.

Neuropathic pain exerts a global burden caused by the lesions in the somatosensory nerve system, including the central and peripheral nervous systems. The mechanisms of nerve injury-induced neuropathic pain involve multiple mechanisms, various signaling pathways, and molecules. Currently, poor efficacy is the major limitation of medications for treating neuropathic pain. Thus, understanding the detailed molecular mechanisms should shed light on the development of new therapeutic strategies for neuropathic pain. Several well-established in vivo pain models were used to investigate the detail mechanisms of peripheral neuropathic pain. Molecular mediators of pain are regulated differentially in various forms of neuropathic pain models; these regulators include purinergic receptors, transient receptor potential receptor channels, and voltage-gated sodium and calcium channels. Meanwhile, post-translational modification and transcriptional regulation are also altered in these pain models and have been reported to mediate several pain related molecules. In this review, we focus on molecular mechanisms and mediators of neuropathic pain with their corresponding transcriptional regulation and post-translational modification underlying peripheral sensitization in the dorsal root ganglia. Taken together, these molecular mediators and their modification and regulations provide excellent targets for neuropathic pain treatment.

Membrane potential oscillations are not essential for spontaneous firing generation in L4 Aβ-afferent neurons after L5 spinal nerve axotomy and are not mediated by HCN channels.

What is the central question of this study? Is spontaneous activity (SA) in L4 dorsal root ganglion (DRG) neurons induced by L5 spinal nerve axotomy associated with membrane potential oscillations in these neurons, and if so, are these membrane oscillations mediated by HCN channels? What is the main finding and its importance? Unlike injured L5 DRG neurons, which have been shown to be incapable of firing spontaneously without membrane potential oscillations, membrane potential oscillations are not essential for SA generation in conducting 'uninjured' L4 neurons, and they are not mediated by HCN channels. These findings suggest that the underlying cellular mechanisms of SA in injured and 'uninjured' DRG neurons induced by spinal nerve injury are distinct. The underlying cellular and molecular mechanisms of peripheral neuropathic pain are not fully understood. However, preclinical studies using animal models suggest that this debilitating condition is driven partly by aberrant spontaneous activity (SA) in injured and uninjured dorsal root ganglion (DRG) neurons, and that SA in injured DRG neurons is triggered by subthreshold membrane potential oscillations (SMPOs). Here, using in vivo intracellular recording from control L4-DRG neurons, and ipsilateral L4-DRG neurons in female Wistar rats that had previously undergone L5 spinal nerve axotomy (SNA), we examined whether conducting 'uninjured' L4-DRG neurons in SNA rats exhibit SMPOs, and if so, whether such SMPOs are associated with SA in those L4 neurons, and whether they are mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels. We found that 7days after SNA: (a) none of the control A- or C-fibre DRG neurons showed SMPOs or SA, but 50%, 43% and 0% of spontaneously active cutaneous L4 Aβ-low threshold mechanoreceptors, Aβ-nociceptors and C-nociceptors exhibited SMPOs, respectively, in SNA rats with established neuropathic pain behaviors; (b) neither SMPOs nor SA in L4 Aβ-neurons was suppressed by blocking HCN channels with ZD7288 (10mgkg-1 , i.v.); and (c) there is a tendency for female rats to show greater pain hypersensitivity than male rats. These results suggest that SMPOs are linked to SA only in some of the conducting L4 Aβ-neurons, that such oscillations are not a prerequisite for SA generation in those L4 A- or C-fibre neurons, and that HCN channels are not involved in their electrogenesis.

Overexpression of GRK6 attenuates neuropathic pain via suppression of CXCR2 in rat dorsal root ganglion.

G protein-coupled kinase (GRK) 6 is a member of the GRK family that mediates agonist-induced desensitization and signaling of G protein-coupled receptors (GPCRs), thus involving in a wide variety of processes including inflammation and nociception. Recent studies have indicated that chemokines play an important role in chronic pain via increased expression of respective GPCRs. This study was designed to investigate the role of GRK6 and its interaction with substrate chemokine receptors in dorsal root ganglion (DRG) in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Following induction of CCI, GRK6 expression was significantly downregulated in rat DRGs at L4-L6 segments. Overexpression of GRK6 using lentiviral-mediated production strategy via sciatic nerve injection markedly attenuated mechanical allodynia and thermal hyperalgesia in CCI rats. Overexpression of GRK6 also drastically reversed the hyperexcitability of DRG neurons innervating the hind paw and suppressed the enhanced expression of CXCR2 in DRGs of CCI rats. In addition, co-immunoprecipitation, immunofluorescence, and correlation analysis supported the interaction between GRK6 and CXCR2. These results suggest that GRK6 might be a key molecular involved in peripheral mechanism of neuropathic pain and that overexpression of GRK6 might be a potential strategy for treatment for neuropathic pain through inhibition of CXCR2 signal pathway.

TRESK gene recombinant adenovirus vector inhibits capsaicin-mediated substance P release from cultured rat dorsal root ganglion neurons

The present study was conducted to determine whether the activation of TRESK in the dorsal root ganglion (DRG) by the TRESK gene recombinant adenovirus vector inhibits the capsaicin-evoked substance P (SP) release using a radioimmunoassay. TRESK is an outwardly rectifying K+ current channel that contributes to the resting potential and is the most important background potassium channel in DRG. Previous studies have shown that neuropathic pain (NP) is closely related to the regulation of certain potassium channels in DRG neurons, while DRG-released SP is important in the peripheral mechanism of NP. In the present study, the TRESK gene adenovirus vector significantly enhanced the TRESK mRNA and protein of the cultured rat DRG neurons. Radioimmunoassay analysis revealed that the capsaicin-mediated SP release was significantly inhibited by the TRESK gene recombinant adenovirus vector in rat DRG neurons. These findings suggest that TRESK plays a role in adjusting the release of SP in DRG, which is related to NP.

Mexiletine suppresses nodal persistent sodium currents in sensory axons of patients with neuropathic pain

To investigate changes in axonal persistent Na(+) currents in patients with neuropathic pain and the effects of mexiletine, an analogue of lidocaine, on axonal excitability properties. The technique of latent addition was used to estimate nodal persistent Na(+) currents in superficial radial sensory axons of 17 patients with neuropathic pain/paresthesias before and after mexiletine treatment. Brief hyperpolarizing conditioning currents were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an indicator of the magnitude of persistent Na(+) currents. Threshold changes at 0.2 ms in latent addition were greater in the neuropathic patients than in the normal controls (p<0.001). After mexiletine treatment, there was a reduction in clinical pain scores (p<0.001), associated with decreased threshold changes at 0.2 ms (p<0.001). In patients with neuropathy, nodal persistent Na(+) currents in large sensory fibers increase, and the abnormal currents can be suppressed by mexiletine. Pain reduction after mexiletine treatment raises the possibility that excessive Na(+) currents are also suppressed in small fibers mediating neuropathic pain. Latent addition can be used for indirect in vivo monitoring of nodal Na(+) currents in large sensory fibers, and future studies using this approach in small fibers would provide new insights into the peripheral mechanism of neuropathic pain.

Mechanisms of peripheral neuropathic pain: implications for musculoskeletal physiotherapy

Physiotherapy has long been part of the overall intervention for the attempted rehabilitation of patients with pain and disability following peripheral (and central) nerve damage. In musculoskeletal physiotherapy (a subspecialty), a movement-based assessment and treatment protocol has been devised that is guided by, among other things, therapists' perceptions of patients' responses to mechanical stimuli, including various tests of 'neural tension'. Recently, this process together with provocative tests of sensation has been employed to identify, and predict outcomes for, patients suspected of having a 'neural tissue' component to their pain and consequent disability (either fascicular damage or 'neuritis'). However, some of the syndromes involved are controversial, and uncertainty still surrounds the diagnosis, mechanisms and, therefore, effective treatment of the highly complex symptom, true neuropathic pain. In this review, the current basic scientific evidence for the proposed cause, and often intractable nature, of neuropathic pain is presented and discussed with reference to musculoskeletal therapy. It will be seen that peripheral nerve damage has the potential to create potentially irreversible changes in (peripheral and) central nervous system structure and function that have, to date, largely defied effective medical treatment. For musculoskeletal physiotherapy to discriminate accurately and, where appropriate, intervene (or not) responsibly, it would seem constructive to incorporate this (and other) mechanisms-related evidence into its clinical reasoning and decision-making process.

Chronic neuropathic pain: mechanisms and treatment. (Hôspital Ambroise Paré, Paris, France) Clin J Pain 2000; 16:S118–S130.

This report presents a brief overview of the mechanisms of peripheral neuropathic pain, which are largely detailed elsewhere, and reviews the current pharmacologic approach to the treatment of neuropathic pain. Nonpharmacologic treatment of neuropathic pain is not addressed in this report.