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The CB R agonist AM1710, examined in animal models of peripheral neuropathy, is effective in controlling aberrant light touch sensitivity, referred to as mechanical allodynia. However, nonspecific binding of AM1710 to CB R, either peripherally or centrally, could be partially responsible for the analgesic effects of AM1710. Thus, we sought to determine in mice whether spinal (intrathecal; i.t.) or peripheral AM1710 administration could lead to anti-allodynia by reducing the protein expression of spinal and dorsal root ganglia (DRG) proinflammatory cytokines and elevating the anti-inflammatory cytokine interleukin-10 (IL-10) in the absence of CB R. Macrophage cell cultures were examined to characterize AM1710-mediated suppression of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Either i.p. or i.t. AM1710 reversed CCI-induced mechanical allodynia to sham levels in CB R (-/-), (+/-), (+/+) mice. CCI-induced neuropathy decreased IL-10 immunoreactivity (IR) in the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord, with i.t. AM1710 restoring basal IL-10 IR. CCI-induced elevations in proinflammatory cytokine IR were decreased within the spinal cord only after i.t. AM1710 in all mouse genotypes. Meanwhile, within DRG tissue from neuropathic mice, proinflammatory cytokines were decreased following either i.p. or i.t. AM1710. Analysis of cultured supernatants revealed AM1710 decreased TNF-alpha protein. We conclude that CB R is dispensable for either peripheral or central anti-allodynic actions of AM1710 in neuropathic mice. Cannabinoid CB R agonists produce heightened spinal IL-10 which may be clinically relevant to successfully treat neuropathic pain.
Learn More >Chronic pain treatment remains a sore challenge, and in our aging society, the number of patients reporting inadequate pain relief continues to grow. Current treatment options all have their drawbacks, including limited efficacy and the propensity of abuse and addiction; the latter is exemplified by the ongoing opioid crisis. Extensive research in the last few decades has focused on mechanisms underlying chronic pain states, thereby producing attractive opportunities for novel, effective and safe pharmaceutical interventions. Members of the transient receptor potential (TRP) ion channel family represent innovative targets to tackle pain sensation at the root. Three TRP channels, TRPV1, TRPM3, and TRPA1, are of particular interest, as they were identified as sensors of chemical- and heat-induced pain in nociceptor neurons. This review summarizes the knowledge regarding TRP channel-based pain therapies, including the bumpy road of the clinical development of TRPV1 antagonists, the current status of TRPA1 antagonists, and the future potential of targeting TRPM3. Expected final online publication date for the , Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >To compare different exercise prescriptions for patients with chronic pain along the continuum of nociplastic pain: fibromyalgia, chronic whiplash-associated disorders (CWAD), and chronic idiopathic neck pain (CINP).
Learn More >Pain is one of the most disabling symptoms in multiple sclerosis. Chronic pain in multiple sclerosis is often neuropathic in nature, although a clear-cut distinction with nociceptive pain is not easy.
Learn More >Acceptance and Commitment Therapy (ACT) is an empirically supported treatment for chronic pain in adults. There is also a small but growing evidence base of ACT for pediatric chronic pain. However, because of limited access to psychological treatment for pain, and geographical distances from pain facilities, many patients will not receive such treatment.
Learn More >We examined the disparities in emergency department (ED) pain treatment based on cognitive status in older adults with an acute hip fracture.
Learn More >Under some conditions, people persist in their attempts to control their pain even when no such control is possible. Theory suggests that such pain-control attempts arise from actual pain experiences. Across three experiments we examined how (a) losing control over pain and (b) instructions concerning pain, moderate pain-control attempts. In each experiment, participants completed a learning task. Before the task, one group of participants received instructions outlining a strategy via which they could control pain, whereas another group had to develop such a strategy via trial-and-error learning. During the first half of the task, the pain-control instructions allowed participants to successfully control pain, while during the second half of the task, this was no longer the case. Instead, participants lost control over pain due to an unannounced change in the learning task. Results indicate that when participants lost control over pain, they generally stuck to the previously effective pain-control strategy, and that this tendency was larger if they received instructions from others than when they developed a strategy by themselves. These findings suggest that when pain is no longer controllable, very persistent pain-control attempts might be the result of adherence to previously effective pain-control instructions.
Learn More >Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM are not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. LPS-evoked and spontaneous secretion of IL-5 and other select cytokines from circulating monocytes was higher in women with FM compared to women without pain. Additionally, greater secretion of IL-5 was significantly associated with pain and other clinically relevant psychological and somatic symptoms of FM. Further, higher levels of pain and pain-related symptoms were associated with a lower percentage of intermediate monocytes (CD14/CD16) and a greater percentage of non-classical monocytes (CD14/CD16) in women with FM. Based on findings from individuals with FM, we examined the role of IL-5, an atypical cytokine secreted from monocytes, in an animal model of widespread muscle pain. Results from the animal model show that IL-5 produces analgesia and polarizes monocytes toward an anti-inflammatory phenotype (CD206). Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 in secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM.
Learn More >The dissemination of cancer to bone can cause significant cancer-induced bone pain (CIBP), severely impairing the patient's quality of life. Several rodent models have been developed to explore the nociceptive mechanisms of CIBP, including intratibial inoculation of breast carcinoma cells in syngeneic Sprague Dawley rats. Using this model, we investigated whether resident spinal microglial cells are involved in the transmission and modulation of CIBP, a long-debated disease feature. Immunohistochemical staining of ionizing calcium-binding adaptor molecule 1 (Iba-1) and phosphorylated p38-mitogen-activated protein kinase (P-p38 MAPK) showed no spinal microglial reaction in cancer-bearing rats, independently of disease stage, sex, or carcinoma cell line. As a positive control, significant upregulation of both Iba-1 and P-p38 was observed in a rat model of neuropathic pain. Additionally, intrathecal administration of the microglial inhibitor minocycline did not ameliorate pain-like behaviors in cancer-bearing rats, in contrast to spinal morphine administration. Our results indicate that microglial reaction is not a main player in CIBP, adding to the debate that even within the same models of CIBP, significant variations are seen in disease features considered potential drug targets. We suggest that this heterogeneity may reflect the clinical landscape, underscoring the need for understanding the translational value of CIBP models.
Learn More >Chronic pain is more common among veterans than among the general population. Expert guidelines recommend multimodal chronic pain care. However, there is substantial variation in the availability and utilization of treatment modalities in the Veterans Health Administration. We explored health care providers' and administrators' perspectives on the barriers to and facilitators of multimodal chronic pain care in the Veterans Health Administration to understand variation in the use of multimodal pain treatment modalities.
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