Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat.

Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKCε), occurs in male but not in female rats. However, activation of second messengers downstream of PKCε, such as the ryanodine receptor, induces priming in both sexes. Since estrogen regulates intracellular calcium, we investigated the interaction between estrogen and ryanodine in the susceptibility to develop priming in females.

Age differences in fatigue, decrements in energy, and sleep disturbance in oncology patients receiving chemotherapy.

Objective: The number of older adults with cancer is increasing. Given the limited amount of research and the inconsistent findings regarding age differences in common physical symptoms associated with cancer and its treatments, the purposes of this study, in a sample of oncology outpatients receiving chemotherapy (CTX), were to evaluate for age differences in demographic and clinical characteristics, as well as in occurrence rates of and severity ratings for fatigue, decrements in energy, and sleep disturbance. In addition, using regression analysis techniques, within and across age groups, demographic and clinical characteristics associated with the severity of each symptom were evaluated.

Translational Insight Into Polycystic Ovary Syndrome (PCOS) From Female Monkeys with PCOS-like Traits.

Genetics-based studies of women with polycystic ovary syndrome (PCOS) implicate >20 PCOS risk genes that collectively account for <10% of PCOS. Clinicians now consider that either rare alleles or non-genetic, potentially epigenetic, developmental origins may contribute key pathogenic components to >90% of PCOS cases. Animal models convincingly demonstrate excess fetal testosterone exposure in females as a reliable, epigenetic, developmental origin for PCOS-like traits.

The Methylcytosine Dioxygenase Ten-Eleven Translocase-2 (tet2) Enables Elevated GnRH Gene Expression and Maintenance of Male Reproductive Function.

Reproduction depends on the establishment and maintenance of elevated GnRH neurosecretion. The elevation of primate GnRH release is accompanied by epigenetic changes. Specifically, cytosine residues within the GnRH gene promoter are actively demethylated, whereas GnRH mRNA levels and peptide release rise.

Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming.

We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming.

Gene Expression Profiling of Evening Fatigue in Women Undergoing Chemotherapy for Breast Cancer.

Moderate-to-severe fatigue occurs in up to 94% of oncology patients undergoing active treatment. Current interventions for fatigue are not efficacious. A major impediment to the development of effective treatments is a lack of understanding of the fundamental mechanisms underlying fatigue.

ERα Signaling Is Required for TrkB-Mediated Hippocampal Neuroprotection in Female Neonatal Mice after Hypoxic Ischemic Encephalopathy(1,2,3).

Male neonate brains are more susceptible to the effects of perinatal asphyxia resulting in hypoxia and ischemia (HI)-related brain injury. The relative resistance of female neonatal brains to adverse consequences of HI suggests that there are sex-specific mechanisms that afford females greater neuroprotection and/or facilitates recovery post-HI. We hypothesized that HI preferentially induces estrogen receptor α (ERα) expression in female neonatal hippocampi and that ERα is coupled to Src family kinase (SFK) activation that in turn augments phosphorylation of the TrkB and thereby results in decreased apoptosis.

Predictors of Altered Upper Extremity Function During the First Year After Breast Cancer Treatment.

Objective: The purpose of this study was to evaluate trajectories of and predictors for changes in upper extremity (UE) function in women (n = 396) during the first year after breast cancer treatment.

Design: Prospective, longitudinal assessments of shoulder range of motion (ROM), grip strength, and perceived interference of function were performed before and for 1 year after surgery. Demographic, clinical, and treatment characteristics were evaluated as predictors of postoperative function.

Estradiol Restrains Prepubertal Gonadotropin Secretion in Female Mice via Activation of ERα in Kisspeptin Neurons.

Elimination of estrogen receptorα (ERα) from kisspeptin (Kiss1) neurons results in premature LH release and pubertal onset, implicating these receptors in 17β-estradiol (E2)-mediated negative feedback regulation of GnRH release during the prepubertal period. Here, we tested the dependency of prepubertal negative feedback on ERα in Kiss1 neurons. Prepubertal (postnatal d 14) and peripubertal (postnatal d 34) wild-type (WT) and Kiss1 cell-specific ERα knockout (KERαKO) female mice were sham operated or ovariectomized and treated with either vehicle- or E2-containing capsules.

Role of Kv4.3 in Vibration-Induced Muscle Pain in the Rat.

Unlabelled: We hypothesized that changes in the expression of voltage-gated potassium channel (Kv) 4.3 contribute to the mechanical hyperalgesia induced by vibration injury, in a rodent model for hand-arm vibration syndrome in humans. Here we show that the exposure of the gastrocnemius muscle to vibration injury induces muscle hyperalgesia that is accompanied by a significant downregulation of Kv4.

Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations.

There is growing concern about lack of scientific rigor and transparent reporting across many preclinical fields of biological research. Poor experimental design and lack of transparent reporting can result in conscious or unconscious experimental bias, producing results that are not replicable. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.

Differences in demographic, clinical, and symptom characteristics and quality of life outcomes among oncology patients with different types of pain.

The purposes of this study, in oncology outpatients receiving chemotherapy (n = 926), were to: describe the occurrence of different types of pain (ie, no pain, only noncancer pain [NCP], only cancer pain [CP], or both CP and NCP) and evaluate for differences in demographic, clinical, and symptom characteristics, and quality of life (QOL) among the 4 groups. Patients completed self-report questionnaires on demographic and symptom characteristics and QOL. Patients who had pain were asked to indicate if it was or was not related to their cancer or its treatment.

Differences in limb volume trajectories after breast cancer treatment.

Purpose: Approximately 20 % of patients develop lymphedema (LE) following breast cancer (BC) surgery. An evaluation of distinct trajectories of volume change may improve our ability to diagnose LE sooner. The purposes of this study were to identify subgroups of women with distinct trajectories of limb volume changes following BC surgery and to evaluate for phenotypic differences among these classes.

Adenosine-A1 receptor agonist induced hyperalgesic priming type II.

We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent.

Contribution of Piezo2 to endothelium-dependent pain.

Background: We evaluated the role of a mechanically-gated ion channel, Piezo2, in mechanical stimulation-induced enhancement of hyperalgesia produced by the pronociceptive vasoactive mediator endothelin-1, an innocuous mechanical stimulus-induced enhancement of hyperalgesia that is vascular endothelial cell dependent. We also evaluated its role in a preclinical model of a vascular endothelial cell dependent painful peripheral neuropathy.

Results: The local administration of oligodeoxynucleotides antisense to Piezo2 mRNA, at the site of nociceptive testing in the rat's hind paw, but not intrathecally at the central terminal of the nociceptor, prevented innocuous stimulus-induced enhancement of hyperalgesia produced by endothelin-1 (100 ng).

Subgroups of chemotherapy patients with distinct morning and evening fatigue trajectories.

Purpose: Purposes of this study were to identify subgroups of patients with distinct trajectories for morning and evening fatigue, evaluate for differences in demographic and clinical characteristics among these subgroups, and compare and contrast the predictors of subgroup membership for morning and evening fatigue.

Methods: Outpatients with breast, gastrointestinal, gynecological, or lung cancer (n = 582) completed questionnaires, a total of six times over two cycles of chemotherapy (CTX). Morning and evening fatigue severity were evaluated using the Lee Fatigue Scale.

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain.

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.

Co-occurrence of anxiety and depressive symptoms following breast cancer surgery and its impact on quality of life.

Purpose: Little is known about the prevalence of combined anxiety and depressive symptoms (CADS) in breast cancer patients. Purpose was to evaluate for differences in demographic and clinical characteristics and quality of life (QOL) prior to breast cancer surgery among women classified into one of four distinct anxiety and/or depressive symptom groups.

Methods: A total of 335 patients completed measures of anxiety and depressive symptoms and QOL prior to and for 6 months following breast cancer surgery.

Comparison of subgroups of breast cancer patients on pain and co-occurring symptoms following chemotherapy.

Purpose: The purposes of this study, in a sample of women with breast cancer receiving chemotherapy (CTX), were to identify subgroups of women with distinct experiences with the symptom cluster of pain, fatigue, sleep disturbance, and depressive symptoms and evaluate differences in demographic and clinical characteristics, differences in psychological symptoms, and differences in pain characteristics among these subgroups.

Methods: Patients completed symptom questionnaires in the week following CTX administration. Latent class profile analysis (LCPA) was used to determine the patient subgroups.

Topical Tetrodotoxin Attenuates Photophobia Induced by Corneal Injury in the Rat.

Corneal injury can produce photophobia, an aversive sensitivity to light. Using topical application of lidocaine, a local anesthetic, and tetrodotoxin (TTX), a selective voltage-sensitive sodium channel blocker, we assessed whether enhanced aversiveness to light induced by corneal injury in rats was caused by enhanced activity in corneal afferents. Eye closure induced by 30 seconds of exposure to bright light (460-485 nm) was increased 24 hours after corneal injury induced by de-epithelialization.

Distinct terminal and cell body mechanisms in the nociceptor mediate hyperalgesic priming.

Hyperalgesic priming, a form of neuroplasticity in nociceptors, is a model of the transition from acute to chronic pain in the rat, which involves signaling from the site of an acute tissue insult in the vicinity of the peripheral terminal of a nociceptor to its cell body that, in turn, induces a signal that travels back to the terminal to mediate a marked prolongation of prostaglandin E2-induced hyperalgesia. In the present experiments, we studied the underlying mechanisms in the cell body and compared them to the mechanisms in the nerve terminal. Injection of a cell-permeant cAMP analog, 8-bromo cAMP, into the dorsal root ganglion induced mechanical hyperalgesia and priming with an onset more rapid than when induced at the peripheral terminal.

Neuronally produced versican V2 renders C-fiber nociceptors IB4 -positive.

A subpopulation of nociceptors, the glial cell line-derived neurotrophic factor (GDNF)-dependent, non-peptidergic C-fibers, expresses a cell-surface glycoconjugate that can be selectively labeled with isolectin B4 (IB4 ), a homotetrameric plant lectin from Griffonia simplicifolia. We show that versican is an IB4 -binding molecule in rat dorsal root ganglion neurons. Using reverse transcriptase polymerase chain reaction (RT-PCR), in situ hybridization and immunofluorescence experiments on rat lumbar dorsal root ganglion, we provide the first demonstration that versican is produced by neurons.

Trajectories of Evening Fatigue in Oncology Outpatients Receiving Chemotherapy.

Context: Fatigue is a distressing persistent sense of physical tiredness that is not proportional to a person's recent activity. Fatigue impacts patients' treatment decisions and can limit their self-care activities. Although significant interindividual variability in fatigue severity has been noted, little is known about predictors of interindividual variability in initial levels and trajectories of evening fatigue severity in oncology patients receiving chemotherapy.

Predictors and Trajectories of Morning Fatigue Are Distinct From Evening Fatigue.

Context: Fatigue is the most common symptom in oncology patients during chemotherapy. Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients.

Objectives: An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue.

Polymorphisms in Tumor Necrosis Factor-α Are Associated With Higher Anxiety Levels in Women After Breast Cancer Surgery.

Introduction: Before and after breast cancer surgery, women have reported varying anxiety levels. Recent evidence has suggested that anxiety has a genetic basis and is associated with inflammation. The purposes of the present study were to identify the subgroups of women with distinct anxiety trajectories; to evaluate for differences in the phenotypic characteristics between these subgroups; and to evaluate for associations between polymorphisms in cytokine genes and subgroup membership.