The journal of pain : official journal of the American Pain Society
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This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules-myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide-Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium- and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. ⋯ The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy.
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Chronic pain is a major symptom in patients with endometriosis, a common gynecologic condition affecting women in their reproductive years. Although many proalgesic substances are produced by endometriosis lesions, experimental evidence supporting their relative roles is still lacking. Furthermore, it is unclear whether these proalgesic agents directly activate nociceptors to induce endometriosis pain. To determine their relative contribution to pain associated with endometriosis, we evaluated the intrathecal administration of oligodeoxynucleotides (ODNs) antisense to messenger RNA for receptors for 3 pronociceptive mediators known to be produced by the ectopic endometrium. Two weeks after the implant of autologous uterine tissue onto the gastrocnemius muscle, local mechanical hyperalgesia was observed in operated rats. Intrathecal antisense ODN targeting messenger RNA for the interleukin 6 receptor-signaling complex subunit glycoprotein 130 and the nerve growth factor tyrosine kinase receptor A, but not their mismatch ODNs, reversibly attenuated mechanical hyperalgesia at the implant site. In contrast, intrathecal antisense ODN targeting the tumor necrosis factor receptor 1, at a dose that markedly inhibited intramuscularly injected tumor necrosis factor alpha, had only a small antihyperalgesic effect in this model. These results indicate the relative contribution of pronociceptive mediators produced by ectopic endometrial tissue to endometriosis pain. The experimental approach presented here provides a novel method to evaluate for the differential contribution of mediators produced by other painful lesions as well as endometriosis lesions as targets for novel treatment of pain syndromes. ⋯ This article presents evidence for the relative contribution of proalgesic mediators to primary hyperalgesia displayed by rats submitted to a model of endometriosis pain. This approach can be used to identify potential targets for the treatment of endometriosis pain.
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The purpose of this systematic review was to examine the outcome of complex regional pain syndrome (CRPS) type 1. We searched MEDLINE, Embase, and PsycINFO for relevant studies and included 18 studies, with 3,991 participants, in this review. The following data were extracted: study details, measurement tools used, and rates or severity scores for the symptoms/signs of CRPS at baseline and follow-up, or in groups of patients with different disease durations. A quality assessment revealed significant limitations in the literature, with many studies using different diagnostic criteria. The 3 prospective studies demonstrated that for many patients, symptoms improve markedly within 6 to 13 months of onset. The 12 retrospective studies had highly heterogeneous findings, documenting lasting impairments in many patients. The 3 cross-sectional studies showed that rates of pain and sensory symptoms were highest among those with the longest duration of CRPS. Additionally, most studies showed that motor symptoms (stiffness and weakness) were the most likely to persist whereas sudomotor and vasomotor symptoms were the most likely to improve. Overall, this suggests that some CRPS patients make a good early recovery whereas others develop lasting pain and disability. As yet little is known about the prognostic factors that might differentiate between these groups. ⋯ We found evidence that many CRPS patients recover within 6 to 13 months, but a significant number experience some lasting symptoms, and some experience chronic pain and disability. The quality of the evidence was poor. Future research should examine the factors associated with recovery and identify those at risk of poor outcomes.
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Patients often fail to attend appointments in chronic pain clinics for unknown reasons. We hypothesized that certain patient characteristics predict failure to attend scheduled appointments, pointing to systematic barriers to accessing chronic pain services for certain underserved populations. We collected retrospective data from a longitudinal observational cohort of patients at an academic pain clinic in Newark, New Jersey. To examine the effect of demographic factors on appointment status, we fit a marginal logistic regression using generalized estimating equations with exchangeable correlation. A total of 1,394 patients with 3,488 total encounters between January 1, 2006, and December 31, 2009, were included. Spanish spoken as a primary language (alternatively Hispanic or other race) and living between 5 and 10 miles from the clinic were associated with reduced odds of arriving for an appointment; making an appointment for a particular complaint such as cancer pain or back pain, an interventional pain procedure scheduled in connection with the appointment, unemployed status, and continuity of care (as measured by office visit number) were associated with increased odds of arriving. Spanish spoken as a primary language and distance to the pain clinic predicted failure to attend a scheduled appointment in our cohort. If these constitute systematic barriers to access, they may be amenable to targeted interventions. ⋯ We identified certain patient characteristics, specifically Spanish spoken as a primary language and geographic distance from the clinic, that predict failure to attend an inner-city chronic pain clinic. These identified barriers to accessing chronic pain services may be modifiable by simple cost-effective interventions.