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Acid-sensing ion channels (ASICs), which act as proton-gating sodium channels, have garnered attention as pharmacological targets. ASIC1a isoform, notably prevalent in the central nervous system, plays an important role in synaptic plasticity, anxiety, neurodegeneration, etc. In the peripheral nervous system, ASIC1a shares prominence with ASIC3, the latter well established for its involvement in pain signaling, mechanical sensitivity, and inflammatory hyperalgesia. However, the precise contributions of ASIC1a in peripheral functions necessitate thorough investigation. To dissect the specific roles of ASICs, peptide ligands capable of modulating these channels serve as indispensable tools. Employing molecular modeling, we designed the peptide targeting ASIC1a channel from the sea anemone peptide Ugr9-1, originally targeting ASIC3. This peptide (A23K) retained an inhibitory effect on ASIC3 (IC50 9.39 µM) and exhibited an additional inhibitory effect on ASIC1a (IC50 6.72 µM) in electrophysiological experiments. A crucial interaction between the Lys23 residue of the A23K peptide and the Asp355 residue in the thumb domain of the ASIC1a channel predicted by molecular modeling was confirmed by site-directed mutagenesis of the channel. However, A23K peptide revealed a significant decrease in or loss of analgesic properties when compared to the wild-type Ugr9-1. In summary, using A23K, we show that negative modulation of the ASIC1a channel in the peripheral nervous system can compromise the efficacy of an analgesic drug. These results provide a compelling illustration of the complex balance required when developing peripheral pain treatments targeting ASICs. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs), which act as proton-gating sodium channels, have garnered attention as pharmacological targets. ASIC1a isoform, notably prevalent in the central nervous system, plays an important role in synaptic plasticity, anxiety, neurodegeneration, etc. In the peripheral nervous system, ASIC1a shares prominence with ASIC3, the latter well established for its involvement in pain signaling, mechanical sensitivity, and inflammatory hyperalgesia. However, the precise contributions of ASIC1a in peripheral functions necessitate thorough investigation. To dissect the specific roles of ASICs, peptide ligands capable of modulating these channels serve as indispensable tools. Employing molecular modeling, we designed the peptide targeting ASIC1a channel from the sea anemone peptide Ugr9-1, originally targeting ASIC3. This peptide (A23K) retained an inhibitory effect on ASIC3 (IC50 9.39 µM) and exhibited an additional inhibitory effect on ASIC1a (IC50 6.72 µM) in electrophysiological experiments. A crucial interaction between the Lys23 residue of the A23K peptide and the Asp355 residue in the thumb domain of the ASIC1a channel predicted by molecular modeling was confirmed by site-directed mutagenesis of the channel. However, A23K peptide revealed a significant decrease in or loss of analgesic properties when compared to the wild-type Ugr9-1. In summary, using A23K, we show that negative modulation of the ASIC1a channel in the peripheral nervous system can compromise the efficacy of an analgesic drug. These results provide a compelling illustration of the complex balance required when developing peripheral pain treatments targeting ASICs.

The medial prefrontal cortex (mPFC) consists of a heterogeneous population of neurons that respond to painful stimuli, and our understanding of how different pain models alter these specific mPFC cell types remains incomplete. A distinct subpopulation of mPFC neurons express prodynorphin (Pdyn+), the endogenous peptide agonist for kappa opioid receptors (KORs). Here, we used whole cell patch clamp for studying excitability changes to Pdyn expressing neurons in the prelimbic region of the mPFC (PLPdyn+ neurons) in mouse models of surgical and neuropathic pain. Our recordings revealed that PLPdyn+ neurons consist of both pyramidal and inhibitory cell types. We find that the plantar incision model (PIM) of surgical pain increases intrinsic excitability only in pyramidal PLPdyn+ neurons one day after incision. Following recovery from incision, excitability of pyramidal PLPdyn+ neurons did not differ between male PIM and sham mice, but was decreased in PIM female mice. Moreover, the excitability of inhibitory PLPdyn+ neurons was increased in male PIM mice, but was with no difference between female sham and PIM mice. In the spared nerve injury model (SNI), pyramidal PLPdyn+ neurons were hyperexcitable at both 3 days and 14 days after SNI. However, inhibitory PLPdyn+ neurons were hypoexcitable at 3 days but hyperexcitable at 14 days after SNI. Our findings suggest different subtypes of PLPdyn+ neurons manifest distinct alterations in the development of different pain modalities and are regulated by surgical pain in a sex-specific manner. Our study provides information on a specific neuronal population that is affected by surgical and neuropathic pain.

Migraine is a common, neurovascular headache disorder with a complex molecular interplay. The involvement of ion channels in the pathogenesis of migraine gathered considerable attention with the findings that different ion channels subfamilies are expressed in trigeminovascular system, the physiological substrate of migraine pain, and several ion channel openers investigated in clinical trials with diverse primary endpoints caused headache as a frequent side effect. High‐conductance (big) calcium‐activated potassium (BKCa) channel is expressed in the cranial arteries and the trigeminal pain pathway. Recent clinical research revealed that infusion of BKCa channel opener MaxiPost caused vasodilation, headache and migraine attack. Thus, BKCa channel is involved in pathophysiological mechanisms underlying headache and migraine, and targeting BKCa channel presents a new potential strategy for migraine treatment. [ABSTRACT FROM AUTHOR]

A common symptom in neuromuscular diseases is pain, which changes human movement in many ways. Using the decomposed electromyographic signal, we investigate the strategy of the brain in recruiting different pools of motor units (MUs) to produce torque during induced muscle pain in terms of firing rate (FR), recruitment threshold (RT) and action potential amplitude (MUAPAMP). These properties were used to define two groups (G1/G2) based on a K-means clusterization method. A 2.0 mL intramuscular hypertonic (6%) or isotonic (0.9%) saline solution was injected to induce pain or act as a placebo during isometric and isokinetic knee extension contractions. While isometric torque decreases after pain induction with hypertonic solution, this does not occur in isokinetic torque. This occurs because the MUs re-organized after the injection of both solutions. This is supported by an increase in RT, in both G1 and G2 MUs. However, when inducing pain with the hypertonic solution, RT increase is exacerbated. In this condition, FR also decreases, while MUAPAMP increases only for G1 MUs. Therefore, this study proposes that the strategy for maintaining force production during pain is to recruit MUs with higher RT and MUAPAMP. [ABSTRACT FROM AUTHOR]

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive therapeutic intervention that is typically used for many years to treat chronic pain in patients who are refractory to pain medications. However, evidence of the efficacy of TENS treatment for neuropathic pain is lacking in humans. To further understand the efficacy of TENS under various intervention conditions and illuminate the current circumstance and future research directions, we systematically reviewed animal studies investigating the efficacy of TENS in relieving pain in neuropathic pain rodent models. We searched the Cochrane Library, EMBASE, MEDLINE (via PubMed), and Web of Science and identified 11 studies. Two meta-analyses were performed. The first meta-analysis showed that a single TENS treatment was capable of temporarily ameliorating neuropathic pain when compared to control groups with a significant effect (standardized mean difference: 1.54; 95% CI: 0.65, 2.42; p = 0.0007; I 2 = 58%). Significant temporary alleviation in neuropathic pain intensity was also observed in the meta-analysis of repetitive TENS (standardized mean difference: 0.85; 95% CI: 0.31, 1.40; p = 0.002; I 2 = 75%). Subgroup analysis showed no effect of the timing of the application of TENS (test for subgroup difference, p = 0.47). Leave-one-out sensitivity analyses suggested that no single study had an outsized effect on the pooled estimates, which may partly prove the robustness of these findings. Other stratified analyses were prevented by the insufficient number of included studies. Overall, current data suggest that TENS might be a promising therapy to ameliorate neuropathic pain. However, the high risk of bias in the included studies suggests that cautions must be considered when interpreting these findings and it is not reasonable to directly generalize the results obtained from animal studies to clinical practice. Future studies should pay more attention to improving the quality of study design and reporting, thereby facilitating the understanding of mechanisms underlying TENS treatment, reducing more potentially unsuccessful clinical trials, and optimizing the efficacy of TENS for people with neuropathic pain. [ABSTRACT FROM AUTHOR]

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive therapeutic intervention that is typically used for many years to treat chronic pain in patients who are refractory to pain medications. However, evidence of the efficacy of TENS treatment for neuropathic pain is lacking in humans. To further understand the efficacy of TENS under various intervention conditions and illuminate the current circumstance and future research directions, we systematically reviewed animal studies investigating the efficacy of TENS in relieving pain in neuropathic pain rodent models. We searched the Cochrane Library, EMBASE, MEDLINE (via PubMed), and Web of Science and identified 11 studies. Two meta-analyses were performed. The first meta-analysis showed that a single TENS treatment was capable of temporarily ameliorating neuropathic pain when compared to control groups with a significant effect (standardized mean difference: 1.54; 95% CI: 0.65, 2.42; p = 0.0007; I2 = 58%). Significant temporary alleviation in neuropathic pain intensity was also observed in the meta-analysis of repetitive TENS (standardized mean difference: 0.85; 95% CI: 0.31, 1.40; p = 0.002; I2 = 75%). Subgroup analysis showed no effect of the timing of the application of TENS (test for subgroup difference, p = 0.47). Leave-one-out sensitivity analyses suggested that no single study had an outsized effect on the pooled estimates, which may partly prove the robustness of these findings. Other stratified analyses were prevented by the insufficient number of included studies. Overall, current data suggest that TENS might be a promising therapy to ameliorate neuropathic pain. However, the high risk of bias in the included studies suggests that cautions must be considered when interpreting these findings and it is not reasonable to directly generalize the results obtained from animal studies to clinical practice. Future studies should pay more attention to improving the quality of study design and reporting, thereby facilitating the understanding of mechanisms underlying TENS treatment, reducing more potentially unsuccessful clinical trials, and optimizing the efficacy of TENS for people with neuropathic pain.

A common symptom in neuromuscular diseases is pain, which changes human movement in many ways. Using the decomposed electromyographic signal, we investigate the strategy of the brain in recruiting different pools of motor units (MUs) to produce torque during induced muscle pain in terms of firing rate (FR), recruitment threshold (RT) and action potential amplitude (MUAPAMP). These properties were used to define two groups (G1/G2) based on a K-means clusterization method. A 2.0 mL intramuscular hypertonic (6%) or isotonic (0.9%) saline solution was injected to induce pain or act as a placebo during isometric and isokinetic knee extension contractions. While isometric torque decreases after pain induction with hypertonic solution, this does not occur in isokinetic torque. This occurs because the MUs re-organized after the injection of both solutions. This is supported by an increase in RT, in both G1 and G2 MUs. However, when inducing pain with the hypertonic solution, RT increase is exacerbated. In this condition, FR also decreases, while MUAPAMP increases only for G1 MUs. Therefore, this study proposes that the strategy for maintaining force production during pain is to recruit MUs with higher RT and MUAPAMP.

The medial prefrontal cortex (mPFC) consists of a heterogeneous population of neurons that respond to painful stimuli, and our understanding of how different pain models alter these specific mPFC cell types remains incomplete. A distinct subpopulation of mPFC neurons express prodynorphin (Pdyn + ), the endogenous peptide agonist for kappa opioid receptors (KORs). Here, we used whole cell patch clamp for studying excitability changes to Pdyn expressing neurons in the prelimbic region of the mPFC (PL Pdyn+ neurons) in mouse models of surgical and neuropathic pain. Our recordings revealed that PL Pdyn+ neurons consist of both pyramidal and inhibitory cell types. We find that the plantar incision model (PIM) of surgical pain increases intrinsic excitability only in pyramidal PL Pdyn+ neurons one day after incision. Following recovery from incision, excitability of pyramidal PL Pdyn+ neurons did not differ between male PIM and sham mice, but was decreased in PIM female mice. Moreover, the excitability of inhibitory PL Pdyn+ neurons was increased in male PIM mice, but was with no difference between female sham and PIM mice. In the spared nerve injury model (SNI), pyramidal PL Pdyn+ neurons were hyperexcitable at both 3 days and 14 days after SNI. However, inhibitory PL Pdyn+ neurons were hypoexcitable at 3 days but hyperexcitable at 14 days after SNI. Our findings suggest different subtypes of PL Pdyn+ neurons manifest distinct alterations in the development of different pain modalities and are regulated by surgical pain in a sex-specific manner. Our study provides information on a specific neuronal population that is affected by surgical and neuropathic pain., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Due to the large volume of surgeries and the subsequent incidence of postsurgical pain, it is vital that the underlying mechanisms of postsurgical pain are thoroughly understood. The intensity of acute postsurgical pain is typically dependent on the severity of tissue damage the surgery produces, and the development of chronic pain is more frequent in major surgeries than in minor ones. It is therefore important that postsurgical pain studies are conducted with the differences between major and minor surgeries in mind. To this end, the paw incision and skin muscle incision and retraction models are the focus of this chapter as they feature aspects observed in minor and major surgeries in humans, respectively. Several elements of these models translate to humans with some limitations, as they allow for the measurement of reflexive, spontaneous, and functional pain-like behavior. For these attributes, the SMIR and paw incision surgeries are widely used in postsurgical pain research. Here we layout detailed protocols to instruct experienced as well as inexperienced researchers studying postsurgical pain in rats and mice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

While cancer patients may have chemotherapeutics to thank for being cured of their malignancy, they are often left to suffer a disabling neuropathy induced by that same cancer treatment. This neuropathy, known as chemotherapy-induced peripheral neuropathy, or CIPN, is one of the most debilitating survivorship concerns for patients, with many citing hallmark symptoms of hyperalgesia, allodynia, and numbness, and subsequently reducing their dose or even ceasing treatment altogether. Investigations into this interplay between the antineoplastic activity of chemotherapeutic agents and the preservation of peripheral nerve health are therefore crucial for the development of CIPN treatment and prevention methods. Responding to need, current literature is inundated with varying preclinical models of CIPN. This chapter thus seeks to provide a detailed and reliable methodology for the induction and assessment of CIPN in mice, using a preclinical model that is both reproducible and translatable to several aspects of the clinical phenotype. Specifically, this chapter lays out a model for intermittent low-dose paclitaxel induction of CIPN in C57BL/6J mice, and a testing of this induction via von Frey filament mechanical hypersensitivity assays, a mechanical hyposensitivity (numbness) assay, and a cold-thermal allodynia assay (acetone test). These protocols can easily be adjusted to fit the needs of individual CIPN experiments, as stated throughout the chapter., (Copyright © 2022 Elsevier Inc. All rights reserved.)