Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content. Pinto-Ribeiro Filipa,Moreira Vitor,Pêgo José M,Leão Pedro,Almeida Armando,Sousa Nuno Molecular pain BACKGROUND:While acute effects of stress on pain are well described, those produced by chronic stress are still a matter of dispute. Previously we demonstrated that chronic unpredictable stress results in antinociception in the tail-flick test, an effect that is mediated by increased levels of corticosteroids. In the present study, we evaluated nociception in rats after chronic treatment with corticosterone (CORT) and dexamethasone (DEX) in order to discriminate the role of each type of corticosteroid receptors in antinociception. RESULTS:Both experimental groups exhibited a pronounced antinociceptive effect after three weeks of treatment when compared to controls (CONT); however, at four weeks the pain threshold in CORT-treated animals returned to basal levels whereas in DEX-treated rats antinociception was maintained. In order to assess if these differences are associated with altered expression of neuropeptides involved in nociceptive transmission we evaluated the density of substance P (SP), calcitonin gene-related peptide (CGRP), somatostatin (SS) and B2-gamma-aminobutiric acid receptors (GABAB2) expression in the spinal dorsal horn using light density measurements and stereological techniques. After three weeks of treatment the expression of CGRP in the superficial dorsal horn was significantly decreased in both CORT and DEX groups, while GABAB2 was significantly increased; the levels of SP for both experimental groups remained unchanged at this point. At 4 weeks, CGRP and SP are reduced in DEX-treated animals and GABAB2 unchanged, but all changes were restored to CONT levels in CORT-treated animals. The expression of SS remained unaltered throughout the experimental period. CONCLUSION:These data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the exclusive GR activation resulted in more profound and sustained behavioural and neurochemical changes, than the one observed with a mixed ligand of corticosteroid receptors. These results might be of relevance for the pharmacological management of certain types of chronic pain, in which corticosteroids are used as adjuvant analgesics. 10.1186/1744-8069-5-41

Identification of mineralocorticoid and glucocorticoid receptors on peripheral nociceptors: Translation of experimental findings from animal to human biology. Tafelski Sascha,Mohamed Doaa,Shaqura Mohammed,Assaf Chalid,Beyer Antje,Treskatsch Sascha,Schäfer Michael,Mousa Shaaban A Brain research Evidence is accumulating that activation of mineralocorticoid (MR) and glucocorticoid (GR) receptors on peripheral sensory neurons modulates pain sensation. While the expression and exact anatomical localization of MR and GR in the various subpopulations of peripheral sensory neurons has been shown in animals, it is still unknown for the human skin. Therefore, we aimed to identify MR and GR mRNA and protein as well as the exact subpopulations of sensory neurons in human versus rat skin. Tissue samples from rat and human skin were subjected to RT-PCR, Western blot and double immunofluorescence confocal analysis of MR and GR with the neuronal markers calcitonin gene-related peptide (CGRP), neurofilament 200 (NF200) and tyrosine hydroxylase (TH). Using RT-PCR we were able to isolate MR as well as GR specific transcripts from human skin. Consistently, Western blot analysis identified MR- as well as GR- specific protein bands at the expected molecular weights of 110 and 87 kD, respectively. Double immunofluorescence confocal microscopy of human skin revealed that MR predominantly colocalized with calcitonin-gene-related peptide (CGRP)-immunoreactive (IR) nociceptive neurons - similar to rat skin - underscoring a pivotal role for MR in the modulation of pain. The majority of GR-immmunoreactivity was localized in peripheral peptidergic CGRP-IR sensory nerve fibers, but in addition on TH-IR sympathetic postganglionic, and NF200-IR myelinated mechanoreceptive nerve fibers, both within human and rat skin. Moreover, GR but not MR were localized in keratinocytes of the epidermal layer of human and rat skin. Overall, our results indicate considerable overlap in sensory neuron expression of MR and GR in humans and rats endorsing a common systems approach in mammals that may modulate the transmission of sensory information by MR and GR activation. 10.1016/j.brainres.2019.02.015

Stress responses: the contribution of prostaglandin E(2) and its receptors. Furuyashiki Tomoyuki,Narumiya Shuh Nature reviews. Endocrinology Stress is a state of physiological or psychological strain caused by adverse stimuli; responses to stress include activation of the sympathetic nervous system, glucocorticoid secretion and emotional behaviors. Prostaglandin E(2) (PGE(2)), acting through its four receptor subtypes (EP1, EP2, EP3 and EP4), is involved in these stress responses. Studies of EP-selective drugs and mice lacking specific EPs have identified the neuronal pathways regulated by PGE(2). In animals with febrile illnesses, PGE(2) acts on neurons expressing EP3 in the preoptic hypothalamus. In illness-induced activation of the hypothalamic-pituitary-adrenal axis, EP1 and EP3 regulate distinct neuronal pathways that converge at the paraventricular hypothalamus. During psychological stress, EP1 suppresses impulsive behaviors via the midbrain dopaminergic systems. PGE(2) promotes illness-induced memory impairment, yet also supports hippocampus-dependent memory formation and synaptic plasticity via EP2 in physiological conditions. In response to illness, PGE(2) is synthesized by enzymes induced in various cell types inside and outside the brain, whereas constitutively expressed enzymes in neurons and/or microglia synthesize PGE(2) in response to psychological stress. Dependent on the type of stress stimuli, PGE(2) released from different cell types activates distinct EP receptors, which mobilize multiple neuronal pathways, resulting in stress responses. 10.1038/nrendo.2010.194