Evaluation of HO-1 enzyme activation in locus coeruleus cells in the aversive effect of pain induced by persistent inflammation in rats

Abstract

Painful sensitivity is a somatovisceral perception that has, in addition to the sensory-discriminative component, common to other sensory modalities, an affective-motivational component, which makes this sensitivity unique to each individual. Among the pain modulation mechanisms, cognitive and emotional aspects are of paramount importance, especially in persistent and chronic pain cases. Most studies on painful sensitivity use animal models as a methodology to assess the sensory-discriminatory component, with few findings involving the affective-motivational aspects. A recent study by our group showed that systemic activation of the heme-oxygenase-carbon monoxide (HO-CO) pathway promotes increased expression of HO-1 in the coeruleus locus, associated with an analgesic effect (Cazuza et al., 2018). Besides, we have shown that activation of the HO-CO pathway in the hippocampus modulates opioid receptors' expression and aversiveness to pain in a model of persistent inflammation (Cazuza et al., In review, 2020). Considering that LC is a region with a high expression for HO-1, with efferences for the hippocampus, and that the modulation of noradrenergic neurons in this region can occur by CO (Pineda et al., 1996), the objective of this project is to investigate the intrinsic circuitry of this region associated with the modulation of persistent pain. For this, we will evaluate whether the expression of the HO-1 enzyme occurs in noradrenergic neurons or glial cells using the immunohistochemistry technique for HO-1 with double labeling for tyrosine hydroxylase (noradrenaline marker) or GFAP (astrocyte marker) ), in rats with persistent inflammation, induced by Complete Freund's Adjuvant treated or not with HO-1 inducer (CoPP) or HO-1 inhibitor (SnPP). Additionally, we intend to investigate whether the HO-1 expression changing in the LC due to persistent inflammation and if these changes would be a consequence of epigenetic modulation, such as, for example, changes in DNA methylation in the promoter and/or regulatory region of the gene HO-1. This goal is being carried out in collaboration with Dr. Helene Fachim from the Salford Royal Foundation Trust and University of Manchester, England, during an internship (3 months in 2021). (AU)