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This paper examines the development of and some logistical and methodological issues surrounding the use of animal models of chronic pain. The first section addresses the emergent move towards mechanism-based and disease-related animal models of chronic pain that has accelerated since the late 1980s following publication of Bennett and Xie's (Pain 33:87-107, 1998) paper on chronic constriction injury of the sciatic nerve and Stein et al.'s (Pharmacol Biochem Behav 31:445-451, 1988) paper on unilateral hind paw inflammation with complete Freund's adjuvant. The discussion covers vast areas of chronic pain models developed over the past 50 years, starting with the numerous neuropathic, inflammatory and central pain models, as well as the growing number of models developed to study various forms of chronic pain from chronic back pain to visceral pain. It also examines the advantages and disadvantages of tonic pain models, mechanism-based and disease-related models of chronic pain, including issues related to the novel discovery of injury- or disease-related pathophysiological processes, the expansion of testing repertoires, and the successes and failures in the translation of analgesic development from animal preclinical models to human chronic pain conditions. The second section addresses experimental design considerations in the implementation of one of the 3Rs for the use of animal models of chronic pain; that is methods employed to reduce the number of animals used. The discussion covers various issues including the advantages and disadvantages of repeated dose designs and within-group drug testing, including incremental dosing schedules, and crossover designs. It also examines concerns surrounding the stability of symptoms and measures, including varying durations of multiple symptoms and the potential development of nociceptive sensitization, as well as possible use-dependent alterations in drug sensitivity and time-dependent changes in pain processes in specific animal models.
Learn More >Prostate cancer and prostatitis are both significant health concerns. A large number of studies have established that the occurrence of the two is closely related. However, the most common prostatitis, type III chronic prostatitis/chronic pelvic pain syndromes (CP/CPPS), is reported to not correlate with the occurrence of prostate cancer. Although the etiology of CP/CPPS is unknown, it may be related to the autoimmune mechanism favored by most studies. Manipulating the immune system and targeting tumor microenvironment are promising new methods for the treatment of prostate cancer. Therefore, this review focuses on the immune cells and cytokines of CP/CPPS and prostate cancer from the perspective of biological immunology and immune microenvironment. We discuss T-regulatory (Treg) and T helper 17 (Th17) cells dysfunction, the abnormal regulation of T helper 1(Th1) and T helper 2 (Th2) cells, macrophages and their related cytokines as key activators in CP/CPPS. In addition, we discuss the roles of Treg and Th17 cells, Th1 and Th2 cells, and related cytokines in modulating prostate cancer progression. This review highlights the concept that immune cells and cytokines provide a research strategy for the etiology of CP/CPPS and offer potentially promising targets for the treatment of prostate cancer.
Learn More >Activity-induced pain is common in those with chronic musculoskeletal pain and limits participation in daily activities and exercise. Our laboratory developed a model of activity-induced pain and shows that depletion of muscle macrophages prevents development of hyperalgesia. Adenosine triphosphate (ATP) is released from fatiguing muscle and activates purinergic receptors (P2X), and P2X4 receptors are expressed on macrophages. We hypothesized that exercise releases ATP to activate P2X4 receptors on muscle macrophages, which subsequently release interleukin-1β (IL-1β) to produce hyperalgesia. In an animal model of activity-induced pain, using male and female C57BL6/J mice, we show increased expression of P2X4 on muscle macrophages, and blockade of P2X4 receptors in muscle prevented development of hyperalgesia. Using a lentivirus expressing an artificial micro-RNA to P2X4 under the control of a CD68 promoter, we decreased expression of P2X4 mRNA in cultured macrophages, decreased expression of P2X4 protein in muscle macrophages in vivo, and prevented development of activity-induced hyperalgesia. We further show that macrophages primed with LPS differentially released IL-1β when treated with ATP in neutral or acidic pH. Lastly, blockade of IL-1β in muscle prevented development of hyperalgesia in this model. Thus, our data suggest that P2X4 receptors could be a valid pharmacological target to control activity-induced muscle pain experienced by patients with chronic musculoskeletal pain.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most debilitating long-term side effects in breast cancer survivors. We conducted a randomized controlled pilot trial to assess the feasibility, safety, and effects of an acupuncture intervention on CIPN in this population.
Learn More >Social environment influences the trajectory of developing opioid use disorder (OUD). Thus, the present study tested the hypothesis that sociability levels will affect the responses to opioids. Mice were tested for their baseline sociability, anxiety levels, pain sensitivities, and their acute locomotor response to 5 mg/kg opioids. Then, they were administered repeatedly with saline, hydrocodone, or morphine (20 mg/kg for 5 days, and then 40 mg/kg for 5 days). Subsequently, they were examined for the expression of locomotor sensitization and retested for the effects of opioids on their sociability, anxiety levels, and pain sensitivity. On the basis of their baseline sociability level, mice were divided into socially avoiding and socially exploring. Socially avoiding and socially exploring mice did not differ in their baseline weight and anxiety sensitivities. Socially avoiding mice had slightly higher baseline heat sensitivity than those in socially exploring mice. Repeated administration of opioids had differential effects in socially avoiding and socially exploring mice. In both social groups, repeated morphine administration had overall stronger effects compared with hydrocodone. Morphine-treated socially exploring mice developed greater locomotor sensitization than those in morphine-treated socially avoiding mice. Morphine-treated socially avoiding mice, but not socially exploring mice, spent more time in the center zone of the open-field test and in the light zone of light/dark boxes, and developed heat hyperalgesia. This study suggests that socially exploring animals are more sensitive to the sensitizing effects of opioids. In contrast, opioids have greater effects on the stress and pain systems of socially avoiding animals. Thus, the underlying mechanisms for developing OUD might differ in individuals with various sociability levels.
Learn More >In literature, osmophobia is reported as a specific migrainous symptom with a prevalence of up to 95%. Despite the International Classification of Headache Disorders 2nd edition proposal of including osmophobia among accompanying symptoms, it was no longer mentioned in the ICHD 3rd edition.
Learn More >It has been proposed that Complex Regional Pain Syndrome (CRPS) is a post-traumatic autoimmune disease. Previously we observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture model and that serum IgM antibodies from fracture mice have pronociceptive effects in muMT fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT fracture mice by measuring hindpaw allodynia and unweighting changes. CRPS serum binding was measured against autoantigens previously identified in the fracture mouse model. Both CRPS patient serum or IgM antibodies had pronociceptive effects in the fracture limb when injected systemically in muMT fracture mice, but normal subject serum and CRPS patient IgG antibodies had no effect. Furthermore, CRPS serum IgM antibodies had pronociceptive effects when injected into the fracture limb hindpaw skin or intrathecally in the muMT fracture mice. Early (1-12 months post injury) CRPS patient (n=20) sera were always pronociceptive after systemic injection and chronic (>12 months post injury) CRPS sera were rarely pronociceptive (2/20 patients), while sera from normal subjects (n=20) and from patients with uncomplicated recoveries from orthopedic surgery and/or fracture (n=15) were never pronociceptive. Increased CRPS serum IgM binding was observed for keratin 16, histone 3.2, gamma actin, and alpha enolase autoantigens. We postulate that CRPS patient IgM antibodies bind to neoantigens in the fracture mouse skin and spinal cord to initiate a regionally restricted pronociceptive complement response potentially contributing to the CRPS disease process.
Learn More >We previously demonstrated that acetaminophen (AcAP) has to be metabolized in the brain by fatty acid amide hydrolase enzyme (FAAH) into AM404 (N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) to recruit CB1 and TRPV1 receptors, responsible for its analgesic effect. However, the brain mechanisms supporting AcAP-induced analgesia remain unknown.
Learn More >A striking and debilitating property of the nervous system is that damage to this tissue can cause chronic intractable pain, which persists long after resolution of the initial insult. This neuropathic form of pain can arise from trauma to peripheral nerves, the spinal cord, or brain. It can also result from neuropathies associated with disease states such as diabetes, human immunodeficiency virus/AIDS, herpes, multiple sclerosis, cancer, and chemotherapy. Regardless of the origin, treatments for neuropathic pain remain inadequate. This continues to drive research into the underlying mechanisms. While the literature shows that dysfunction in numerous loci throughout the CNS can contribute to chronic pain, the spinal cord and in particular inhibitory signalling in this region have remained major research areas. This review focuses on local spinal inhibition provided by dorsal horn interneurons, and how such inhibition is disrupted during the development and maintenance of neuropathic pain.
Learn More >In the pain field, it is essential to quantify nociceptive responses. The response to the application of von Frey filaments to the skin measures tactile sensitivity and is a surrogate marker of allodynia in states of peripheral and/or central sensitization. The method is widely used across species within the pain field. However, uncertainties appear to exist regarding the appropriate method for analysing obtained data. Therefore, there is a need for refinement of the calculations for transformation of raw data to quantifiable data.
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