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Preclinical evidence has highlighted the importance of the μ-opioid peptide (MOP) receptor on primary afferents for both the analgesic actions of MOP receptor agonists, as well as the development of tolerance, if not opioid-induced hyperalgesia. There is also growing interest in targeting other opioid peptide receptor subtypes (δ-opioid peptide [DOP], κ-opioid peptide [KOP], and nociceptin/orphanin-FQ opioid peptide [NOP]) on primary afferents, as alternatives to MOP receptors, which may not be associated with as many deleterious side effects. Nevertheless, results from several recent studies of human sensory neurons indicate that although there are many similarities between rodent and human sensory neurons, there may also be important differences. Thus, the purpose of this study was to assess the distribution of opioid receptor subtypes among human sensory neurons. A combination of pharmacology, patch-clamp electrophysiology, Ca imaging, and single-cell semiquantitative polymerase chain reaction was used. Our results suggest that functional MOP-like receptors are present in approximately 50% of human dorsal root ganglion neurons. δ-opioid peptide-like receptors were detected in a subpopulation largely overlapping that with MOP-like receptors. Furthermore, KOP-like and NOP-like receptors are detected in a large proportion (44% and 40%, respectively) of human dorsal root ganglion neurons with KOP receptors also overlapping with MOP receptors at a high rate (83%). Our data confirm that all 4 opioid receptor subtypes are present and functional in human sensory neurons, where the overlap of DOP, KOP, and NOP receptors with MOP receptors suggests that activation of these other opioid receptor subtypes may also have analgesic efficacy.
Learn More >Glucagon-like peptide-1 receptor has anti-apoptotic, anti-inflammatory, and neuroprotective effects. It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses; however, it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms. We explored the effects of glucagon-like peptide-1 receptor on nociception, cognition, and neuroinflammation in chronic pain. A rat model of chronic pain was established using left L5 spinal nerve ligation. The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation. Electrophysiological examinations showed that, after treatment with exendin-4, paw withdrawal frequency of the left limb was significantly reduced, and pain was relieved. In addition, in the Morris water maze test, escape latency increased and the time to reach the platform decreased following exendin-4 treatment. Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus, as well as an increase in the expression of tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6. All of these effects could be reversed by exendin-4 treatment. These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China (approval No. WDRM 20171214) on September 22, 2017.
Learn More >Chronic neck pain is reportedly considered the fourth leading cause of disability. Cervical interlaminar epidural injections are among the commonly administered nonsurgical interventions for managing chronic neck pain, secondary to disc herniation and radiculitis, spinal stenosis, or chronic neck pain of discogenic origin.
Learn More >Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin-4 and interleukin-13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD), but dupilumab effects in Japanese patients have not been reported.
Learn More >Previous reports show that moderate prenatal alcohol exposure (PAE) poses a risk factor for developing neuropathic pain following adult-onset peripheral nerve injury in male rats. Recently, evidence suggests that immune-related mechanisms underlying neuropathic pain in females are different compared to males despite that both sexes develop neuropathy of similar magnitude and duration following chronic constriction injury (CCI) of the sciatic nerve. Data suggest that the actions of peripheral T cells play a greater role in mediating neuropathy in females. The goal of the current study is to identify specificity of immune cell and cytokine changes between PAE and non-PAE neuropathic females by utilizing a well-characterized rodent model of sciatic nerve damage, in an effort to unmask unique signatures of immune-related factors underlying the risk of neuropathy from PAE. Cytokines typically associated with myeloid cell actions such as interleukin (IL)-1β, tumor necrosis factor (TNF), IL-6, IL-4 and IL-10 as well as the neutrophil chemoattractant CXCL1, are examined. In addition, transcription factors and cytokines associated with various differentiated T cell subtypes are examined (anti-inflammatory FOXP3, proinflammatory IL-17A, IL-21, ROR-γt, interferon (IFN)-γ and T-bet). Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule expressed on peripheral immune cells including T cells and regulates T cell activation and extravasation into inflamed tissue regions. A potential therapeutic approach was explored with the goal of controlling proinflammatory responses in neuroanatomical regions critical for CCI-induced allodynia by blocking LFA-1 actions using BIRT377. The data show profound development of hindpaw allodynia in adult non-PAE control females following standard CCI, but not following minor CCI, while minor CCI generated allodynia in PAE females. The data also show substantial increases in T cell-associated proinflammatory cytokine mRNA and proteins, along with evidence of augmented myeloid/glial activation (mRNA) and induction of myeloid/glial-related proinflammatory cytokines, CCL2, IL-1β and TNF in discrete regions along the pain pathway (damaged sciatic nerve, dorsal root ganglia; DRG, and spinal cord). Interestingly, the characteristic anti-inflammatory IL-10 protein response to nerve damage is blunted in neuropathic PAE females. Moreover, T cell profiles are predominantly proinflammatory in neuropathic Sac and PAE females, augmented levels of Th17-specific proinflammatory cytokines IL-17A and IL-21, as well as the Th1-specific factor, T-bet, are observed. Similarly, the expression of RORγt, a critical transcription factor for Th17 cells, is detected in the spinal cord of neuropathic females. Blocking peripheral LFA-1 actions with intravenous (i.v.) BIRT377 reverses allodynia in Sac and PAE rats, dampens myeloid (IL-1β, TNF, CXCL1)- and T cell-associated proinflammatory factors (IL-17A and RORγt) and spinal glial activation. Moreover, i.v. BIRT377 treatment reverses the blunted IL-10 response to CCI observed only in neuropathic PAE rats and elevates FOXP3 in pain-reversed Sac rats. Unexpectedly, intrathecal BIRT377 treatment is unable to alter allodynia in either Sac or PAE neuropathic females. Together, these data provide evidence that: 1) fully differentiated proinflammatory Th17 cells recruited at the sciatic nerve, DRGs and lumbar spinal cord may interact with the local environment to shape the immune responses underlying neuropathy in female rats, and, 2) PAE primes peripheral and spinal immune responses in adult females. PAE is a risk factor in females for developing peripheral neuropathy after minor nerve injury.
Learn More >Nerve injury-induced change in gene expression in primary sensory neurons of dorsal root ganglion (DRG) is critical for neuropathic pain genesis. N-methyladenosine (mA) modification of RNA represents an additional layer of gene regulation. Here, it is reported that peripheral nerve injury increases the expression of the mA demethylase fat-mass and obesity-associated proteins (FTO) in the injured DRG via the activation of Runx1, a transcription factor that binds to the gene promoter. Mimicking this increase erases mA in euchromatic histone lysine methyltransferase 2 () mRNA (encoding the histone methyltransferase G9a) and elevates the level of G9a in DRG and leads to neuropathic pain symptoms. Conversely, blocking this increase reverses a loss of mA sites in mRNA and destabilizes the nerve injury-induced G9a upregulation in the injured DRG and alleviates nerve injury-associated pain hypersensitivities. FTO contributes to neuropathic pain likely through stabilizing nerve injury-induced upregulation of G9a, a neuropathic pain initiator, in primary sensory neurons.
Learn More >Chronic neuropathic pain was an intractable clinical problem and challenge to the quality of life of patients. It is essential to unveil the mechanisms that drive chronic pain so as to formulate new strategies for therapy of chronic pain. The medial prefrontal context (mPFC) plays a pivotal role in pathogenesis of chronic pain. However, its underlying molecular mechanisms are largely elusive. Herein, we demonstrated that mitogen-activated protein kinase-phosphatase1 (MKP1), a negative regulatory factor of mitogen activated protein kinases (MAPKs), was activated and persistently upregulated in the mPFC neurons by qPCR and western blotting assays following chronic constrictive injury (CCI) in mice. Inhibition of MKP1 in the mPFC contralateral to the injury site could reverse CCI-induced pain behavior and neuronal activity either via employment of BCI (MKP1 antagonist) or Lenti-MKP1 particles. Furthermore, we identified the substrates of MKP1 in the mPFC involved in chronic neuropathic pain. The western blot results showed that the phosphorylation of p38 and JNK1/2 was significantly decreased after CCI, while the phosphorylation of ERK1/2 was significantly increased, suggesting that p38 and JNK1/2 were the substrates of MKP1 in mouse mPFC, but not ERK1/2. Additionally, microinjection of BCI in the mPFC contralateral to the injury side could reverse downregulation of p- p38 and p- JNK1/2 in CCI mice. SB203580 (p38 inhibitor) or SP600125 (JNK1/2 inhibitor) could reverse BCI-induced analgesia. Our findings validated that MKP1 in the mPFC modulated chronic neuropathic pain via p38 and JNK1/2, suggesting a possible MKP1-mediated process would participate in neuronal transmission pathways implicated in pain modulation.
Learn More >Alexithymia, or difficulty identifying and describing emotions and sensations, contributes to an increased risk of chronic pain, and low help-seeking. To investigate whether family caregivers of advanced cancer patients visiting a palliative care department had alexithymia, and whether this was related to their pain intensity, personalized pain goals, and help-seeking for chronic musculoskeletal pain. A single-center cross-sectional survey. Pain intensity was evaluated using a numerical rating scale. Pain improvement was evaluated against personal goals. Alexithymia was assessed using the Toronto Alexithymia Scale-20 (TAS-20), and anxiety and depression using the Hospital Anxiety and Depression Scale. Of 320 family caregivers visiting the palliative care department, 152 (47.5%) had chronic musculoskeletal pain; all 152 were included in the study. Alexithymia was observed in 36.2% of participants. Participants with higher scores on the TAS-20 tended to have higher pain intensity scores and personal pain goal scores. TAS-20 score had the strongest correlation with personal pain goals, with a correlation coefficient of 0.555 ( < 0.001). Pain intensity in family caregivers with alexithymia tended to be high. These participants set higher personal pain goals (lower goals for symptom improvement) than those without alexithymia. We found no difference in personal pain goal response between family caregivers with and without alexithymia. When we examine pain in family members with alexithymia who are caring for cancer patients, we need to recognize that they may set higher personal pain goals and seek less help.
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