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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.

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.

Supplemental Digital Content is Available in the Text., In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.

Simple Summary It is difficult to measure pain in horses. As animals are not able to verbalize what they feel, we are left with trying to interpret the different signs that they display when they are in pain. Many of these signs are vague (e.g., not eating their food), but some are more readily identified if the animal moves away or lifts their leg when pressure is applied to a sensitive area. Pressure algometry is a tool used to detect responses to applied mechanical stimuli within painful and nonpainful tissues. Pressure algometry has been used in many different studies, but there is no consensus on how to synthesize this information to better diagnose and treat pain in horses. The purpose of this study was to summarize the results of these studies. Based on that review, we conclude that there is good evidence that pressure algometry is a reliable and objective method to measure pain responses. This information will help to improve the diagnosis and treatment of pain in horses. Abstract The clinical assessment of pain is subjective; therefore, variations exist between practitioners in their ability to identify and localize pain. Due to differing interpretations of the signs or severity of pain equine practitioners may assign varying levels of clinical significance and treatment options. There is a critical need to develop better tools to qualify and quantify pain in horses. Palpation is the most common method to detect local tenderness or sensitivity. To quantify this applied pressure, pressure algometry has been used to gradually apply pressure over specified landmarks until an avoidance response is noted, which is defined as the mechanical nociceptive threshold (MNT). Numerous studies have used pressure algometry in different applications to measure MNTs in horses. There is an acute need to establish normative values within different body regions and to develop standardized methods of testing MNTs to better guide practitioners in the diagnosis and treatment of pain. The aim of this systematic review was to summarize the evidence for the use of pressure algometry in horses. There is good evidence that pressure algometry is a repeatable, semi-objective method that can be used in a wide array of clinical and research applications to assess MNTs in horses.

Highlights • A large proportion of analgesics fail to translate from rodents to humans. • Large animals share anatomical and behavioral similarities to humans. • Studying large animals can provide novel insights for arthritic pain. • In vitro techniques developed in rodents can be adopted in large animals., Pain arising from musculoskeletal disorders such as arthritis is one of the leading causes of disability. Whereas the past 20-years has seen an increase in targeted therapies for rheumatoid arthritis (RA), other arthritis conditions, especially osteoarthritis, remain poorly treated. Although modulation of central pain pathways occurs in chronic arthritis, multiple lines of evidence indicate that peripherally driven pain is important in arthritic pain. To understand the peripheral mechanisms of arthritic pain, various in vitro and in vivo models have been developed, largely in rodents. Although rodent models provide numerous advantages for studying arthritis pathogenesis and treatment, the anatomy and biomechanics of rodent joints differ considerably to those of humans. By contrast, the anatomy and biomechanics of joints in larger animals, such as dogs, show greater similarity to human joints and thus studying them can provide novel insight for arthritis research. The purpose of this article is firstly to review models of arthritis and behavioral outcomes commonly used in large animals. Secondly, we review the existing in vitro models and assays used to study arthritic pain, primarily in rodents, and discuss the potential for adopting these strategies, as well as likely limitations, in large animals. We believe that exploring peripheral mechanisms of arthritic pain in vitro in large animals has the potential to reduce the veterinary burden of arthritis in commonly afflicted species like dogs, as well as to improve translatability of pain research into the clinic.

Effective treatment for many pain disorders is still lacking, which is due to the complexity of pain in general and of the underlying pathology of many pain syndromes in particular. This results in the majority of investigational analgesic drugs failing to reach registration, either due to lack of efficacy, or due to the drug's adverse effect profile. To increase the number of analgesics that reach the patient, it is essential to carefully and rationally plan the clinical development program. By including proof-of-mechanism (PoM) and/or proof-of-concept (PoC) methods in early-phase clinical drug studies, the analgesic drug developer will be better informed regarding the key characteristics of the studied drug, which will aid in making crucial decisions during the development process. Here, we describe the top 10 currently most developed analgesic drug classes, link them mechanistically to appropriate methods to demonstrate PoM and PoC in early-phase clinical trials, and include pros and cons of each of the methods described. Lastly, we discuss how each analgesic drug class requires a tailored experimental approach for proper evaluation of PoM and PoC, and how this can contribute to an efficient and question-based approach in early-phase analgesic drug research.

Orofacial pain conditions are often very debilitating to the patient and difficult to treat. While clinical interest is high, the proportion of studies performed in the orofacial region in laboratory animals is relatively low, compared with other body regions. This is partly due to difficulties in testing freely moving animals and therefore lack of reliable testing methods. Here we present a comprehensive review of the currently used rodent models of inflammatory and neuropathic pain adapted to the orofacial areas, taking into account the difficulties and drawbacks of the existing approaches. We examine the available testing methods and procedures used for assessing the behavioral responses in the face in both mice and rats and provide a summary of some pharmacological agents used in these paradigms to date. The use of these agents in animal models is also compared with outcomes observed in the clinic.

A significant fraction of patients with herpes zoster, caused by Varicella Zoster Virus (VZV), experience chronic pain termed postherpetic neuralgia (PHN). VZV-inoculated rats develop prolonged nocifensive behaviors and serve as a model of PHN. We demonstrate that primary rat cultures show a post-entry block for VZV replication, suggesting the rat is not fully permissive. However, footpads of VZV infected animals show reduced peripheral innervation and innervating dorsal root ganglia (DRG) contained VZV DNA and transcripts of candidate immediate early and early genes. The VZV-infected DRG showed changes in host gene expression patterns, with 84 up-regulated and 116 down-regulated genes seen in gene array studies. qRT-PCR validated the modulation of nociception-associated genes Ntrk2, Trpv1, and Calca (CGRP). The data suggests that VZV inoculation of the rat results in a single round, incomplete infection that is sufficient to induce pain behaviors, and this involves infection of and changes induced in neuronal populations.

Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2) in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2-knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate-induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain.

Human experimental pain models are essential in understanding the pain mechanisms and appear to be ideally suited to test analgesic compounds. The challenge that confronts both the clinician and the scientist is to match specific treatments to different pain-generating mechanisms and hence reach a pain treatment tailored to each individual patient. Experimental pain models offer the possibility to explore the pain system under controlled settings. Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or chemical) can be applied to the skin, muscles, and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multimodel-multistructure testing, the nociception arising from different body structures can be explored and modulation of specific biomarkers by new and existing analgesic drugs can be profiled. The value of human experimental pain models is to link animal and clinical pain studies, providing new possibilities for designing successful clinical trials. Spontaneous pain, the main compliant of the neuropathic patients, but currently there is no human model available that would mimic chronic pain. Therefore, current human pain models cannot replace patient studies for studying efficacy of analgesic compounds, although being helpful for proof-of-concept studies and dose finding.

We sought an optimal method for targeted delivery into dorsal root ganglia (DRGs) for experimental studies, in terms of precision of delivery and avoidance of behavioral disturbances. We examined three approaches for injection into rat DRGs: percutaneous injection without surgical exposure, injection after deep exposure, and injection following deep exposure and partial laminectomy. Coomassie blue and Fast Blue were injected into DRGs for validation. At necropsy, the spread of Coomassie blue and Fast Blue was investigated under stereomicroscope and fluorescent microscope, respectively. We found that percutaneous approach did not provide any successful DRG injections. Deep exposure prior to intraganglionic injection provided variable results, but intraganglionic injection after deep exposure plus partial laminectomy was successful in 100% of attempts. Our subsequent skeletal analysis showed that the anatomical location of DRG is not compatible with successful DRG injection without surgical exposure. Neither of the methods using surgical exposure caused behavioral disturbances. Based on these results we conclude that partial laminectomy offers the most precise method of injecting DRG and does not produce behavioral evidence of nerve damage. Intraganglionic injection after deep exposure alone is less predictable, while percutaneous approaches only allow injection in the peripheral nerve.

Poster ID: 1037210

Poster ID: 1038281

Poster ID: 1019771 Poster ID: 1019771

The experience of pain is variable among certain cultures, ethnical groups and among individuals. This variability can be explained by environmental influence, genetic predisposition and plasticity of the existing neuronal pathways. The purpose of this study was to examine a strain-related difference in pain sensitivity between Wistar and Sprague-Dawley rats strains and if there was a difference, could it be overcomes with the robust test. Mechanical sensitivity e.g. existence of paw withdrawal and complex hyperalgesia-type response after needle stimuli has been measured. Both hindpaws (middle, medial and lateral part) were stimulated randomly in appropriate intervals. The results did not demonstrate statistically significant strain difference in pain sensitivity, except in the lateral part of the hindpaw where Sprague-Dawley rats were more sensitive. This data emphasize the importance of selecting a robust behavior test that will be used in investigation of peripheral nerve injury and in neuropathic pain research.