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Neuraxial Cytokines in Pain States.

ABSTRACT: A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

SUBMITTER: Goncalves Dos Santos G

PROVIDER: S-EPMC6997465 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Neuraxial Cytokines in Pain States.

Gonçalves Dos Santos Gilson G Delay Lauriane L Yaksh Tony L TL Corr Maripat M

Frontiers in immunology 20200128

A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding ...[more]

PMID: 32047493

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Project description:ImportanceNeuraxial labor analgesia is recognized as the most effective method of providing pain relief during labor. Little is known about variation in the rates of neuraxial analgesia across US states. Identifying the presence and extent of variation may provide insights into practice variation and may indicate where access to neuraxial analgesia is inadequate.ObjectiveTo test the hypothesis that variation exists in neuraxial labor analgesia use among US states.Design, setting, and participantsRetrospective, population-based, cross-sectional analysis using US birth certificate data. Participants were 2?625?950 women who underwent labor in 2015.Main outcomes and measuresState-specific prevalence of neuraxial analgesia per 100 women who underwent labor and variability in neuraxial analgesia use among states, assessed using multilevel multivariable regression modeling with the median odds ratio and the intraclass correlation coefficient to evaluate variation by state.ResultsIn the study population of 2?625?950 women, 0.1% (n?=?2010) were younger than 15 years, 7.0% (n?=?183 546) were between the ages of 15 and 19 years, 23.6% (n?=?620 118) were between the ages of 20 and 24 years, 29.6% (n?=?777 957) were between the ages of 25 and 29 years, 26.0% (n?=?683 656) were between the ages of 30 and 34 years, 11.4% (n?=?298 237) were between the ages of 35 and 39 years, 2.2% (n?=?57 130) were between the ages of 40 and 44 years, and 0.1% (n?=?3296) were between the ages of 45 and 54 years. More than 90% were privately insured or insured with Medicaid. Neuraxial analgesia was used by 73.1% (n?=?1?920?368) of women. After adjustment for antepartum, obstetric, and intrapartum factors, Maine had the lowest neuraxial analgesia prevalence (36.6%; 95% CI, 33.2%-40.1%) and Nevada the highest (80.1%; 95% CI, 78.3%-81.7%). The adjusted median odds ratio was 1.5 (95% CI, 1.4-1.6), and the intraclass correlation coefficient was 5.4% (95% CI, 4.0%-7.9%).Conclusions and relevanceResults of this study suggest that a small portion of the overall variation in neuraxial analgesia use is explained by US states. Unmeasured patient-level and hospital-level factors likely account for a large portion of the variation between states. Efforts should be made to understand what the main reasons are for this variation and whether the variation influences maternal or perinatal outcomes.

Project description:BackgroundProviding continuous health insurance coverage during the perinatal period may increase access to and utilization of labor neuraxial analgesia. This study tested the hypothesis that implementation of the 2010 Dependent Coverage Provision of the Patient Protection and Affordable Care Act, requiring private health insurers to allow young adults to remain on their parent's plan until age 26 yr, was associated with increased labor neuraxial analgesia use.MethodsThis study used a natural experiment design and birth certificate data for spontaneous vaginal deliveries in 28 U.S. states between 2009 and 2013. The intervention was the Dependent Coverage Provision, categorized into pre- and postintervention periods (January 2009 to August 2010 and September 2010 to December 2013, respectively). The exposure was women's age, categorized as exposed (21 to 25 yr) and unexposed (27 to 31 yr). The outcome was the labor neuraxial analgesia utilization rate.ResultsOf the 4,515,667 birth certificates analyzed, 3,033,129 (67.2%) indicated labor neuraxial analgesia use. For women aged 21 to 25 yr, labor neuraxial analgesia utilization rates were 64.9% during the preintervention period and 68.9% during the postintervention period (difference, 4.0%; 95% CI, 3.9 to 4.2). For women aged 27 to 31 yr, labor neuraxial analgesia utilization rates were 64.9% during the preintervention period and 67.7% during the postintervention period (difference, 2.8%; 95% CI, 2.7 to 2.9). After adjustment, implementation of the Dependent Coverage Provision was associated with a 1.0% (95% CI, 0.8 to 1.2) absolute increase in labor neuraxial analgesia utilization rate among women aged 21 to 25 yr compared with women aged 27 to 31 yr. The increase was statistically significant for White and Hispanic women but not for Black and Other race and ethnicity women.ConclusionsImplementation of the Dependent Coverage Provision was associated with a statistically significant increase in labor neuraxial analgesia use, but the small effect size is unlikely of clinical significance.Editor’s perspective

Project description:Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.

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Neuraxial Cytokines in Pain States.

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Neuraxial Cytokines in Pain States.

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