Effects of treatment with a carbon monoxide donor and an activator of heme oxygenase 1 on the nociceptive, apoptotic and/or oxidative alterations induced by persistent inflammatory pain in the central nervous system of mice.

The activation of heme oxygenase 1 (HO-1)/carbon monoxide (CO) inhibits chronic inflammatory pain, but its role in the central nervous system (CNS) is not entirely known. We evaluated whether the treatment with an HO-1 inducer, cobalt protoporphyrin IX (CoPP), or a CO-releasing molecule, tricarbonyldichlororuthenium(II)dimer (CORM-2), modulates the nociceptive, apoptotic and/or oxidative responses provoked by persistent inflammatory pain in the CNS. In C57BL/6 male mice with peripheral inflammation caused by complete Freund's adjuvant (CFA), we assessed the effects of CORM-2 and CoPP on the expression of protein kinase B (Akt), the apoptotic protein BAX, and the antioxidant enzymes HO-1 and NADPH quinone oxidoreductase 1 (NQO1) in the periaqueductal gray matter (PAG), amygdala (AMG), ventral hippocampus (VHPC) and medial septal area (MSA). Our results showed that the increased expression of p-Akt caused by peripheral inflammation in the four analyzed brain areas was reversed by CORM-2 and CoPP therapies. Both treatments also normalized the upregulation of BAX induced by CFA on the VHPC and MSA. Oxidative stress, demonstrated with the decreased expression of HO-1 on the PAG and AMG, was normalized in CORM-2 and CoPP treated animals. CoPP also increased the expression of HO-1 on VHPC, and both treatments up-regulated the NQO1 levels on the PAG of CFA-injected animals. In conclusion, both CORM-2 and CoPP treatments inhibited the nociceptive and apoptotic responses generated by peripheral inflammation and/or potentiated the antioxidant responses in several brain areas revealing the new modulatory effects of these treatments in the CNS of animals with chronic inflammatory pain.

HO-CO pathway activation may be associated with hippocampal µ and δ opioid receptors in inhibiting inflammatory pain aversiveness and nociception in WT but not NOS2-KO mice.

Carbon monoxide (CO) and nitric oxide (NO) modulate inflammatory nociception and anxiety. We evaluate whether treatments with a heme oxygenase-1 (HO-1) inducer (CoPP) or a carbon monoxide-releasing molecule (CORM-2) are capable of inhibiting inflammatory pain aversiveness in wild type (WT) and inducible nitric oxide synthase-knock out (NOS2-KO) mice with persistent inflammation and its relationship with µ- (MOR) and δ- (DOR) opioid receptors. WT and NOS2-KO male mice with complete Freund's adjuvant (CFA) injected into the hind paw were evaluated in the von Frey and the escape-avoidance paradigm (PEAP) tests, at 10 days, before and after the treatment with CORM-2 (5 mg/kg) or CoPP (2.5 mg/kg). WT mice groups treated with CORM-2 or CoPP also received naloxone (NLX, a non-specific opioid receptor antagonist). The HO-1, neuronal nitric oxide synthase, NOS2, MOR, and DOR expression in the dorsal hippocampus were evaluated by western blot. CFA reduced mechanical threshold in WT and NOS2-KO mice but only increased the percentage of time in the light compartment in the PEAP in WT mice. CORM-2 and CoPP inhibited these effects in both strains. Pre-treatment with NLX reverses the anti-allodynic and anti-aversive effects of CORM-2 or CoPP in WT mice. CORM-2 and CoPP increases the protein levels of HO-1, MOR and DOR in the dorsal hippocampus of WT mice but not in NOS2-KO animals. Results showed that HOCO pathway activation promotes anti-allodynic effects and reduced pain aversiveness caused by peripheral inflammation by increasing the expression of MOR and DOR activated by HO-1 in the dorsal hippocampus.

Neuroinflammation in the NTS is associated with changes in cardiovascular reflexes during systemic inflammation.

BACKGROUND: Lipopolysaccharide (LPS)-induced systemic inflammation (SI) is associated with neuroinflammation in the brain, hypotension, tachycardia, and multiple organs dysfunctions. Considering that during SI these important cardiovascular and inflammatory changes take place, we measured the sensitivity of the cardiovascular reflexes baroreflex, chemoreflex, and Bezold-Jarisch that are key regulators of hemodynamic function. We also evaluated neuroinflammation in the nucleus tractus solitarius (NTS), the first synaptic station that integrates peripheral signals arising from the cardiovascular and inflammatory status. METHODS: We combined cardiovascular recordings, immunofluorescence, and assays of inflammatory markers in male Wistar rats that receive iv administration of LPS (1.5 or 2.5 mg kg-1) to investigate putative interactions of the neuroinflammation in the NTS and in the anteroventral preoptic region of the hypothalamus (AVPO) with the short-term regulation of blood pressure and heart rate. RESULTS: LPS induced hypotension, tachycardia, autonomic disbalance, hypothermia followed by fever, and reduction in spontaneous baroreflex gain. On the other hand, during SI, the bradycardic component of Bezold-Jarisch and chemoreflex activation was increased. These changes were associated with a higher number of activated microglia and interleukin (IL)-1ß levels in the NTS. CONCLUSIONS: The present data are consistent with the notion that during SI and neuroinflammation in the NTS, rats have a reduced baroreflex gain, combined with an enhancement of the bradycardic component of Bezold-Jarisch and chemoreflex despite the important cardiovascular impairments (hypotension and tachycardia). These changes in the cardiac component of Bezold-Jarisch and chemoreflex may be beneficial during SI and indicate that the improvement of theses reflexes responsiveness though specific nerve stimulations may be useful in the management of sepsis.

Independence of egocentric and exocentric direction processing in visual space

One major issue concerning investigations of visual perception is determination of the geometrical properties of visual space. To address this issue, one must determine the relationships between geometrical features of visual space, distance, direction, angle, and size. Consistent evidence indicates that visual angle is a determinant of perceived exocentric distance. Previous evidence suggests that exocentric distance and direction are hierarchically processed, with distance preceding direction. The present study investigated the relationship between the perceptual processing of egocentric direction and exocentric direction using a task that independently provides both perceptual variables in a single judgment. The results indicated that egocentric directions were systematically overestimated, and this was not caused by either the global shape of the layout or leg length effects. Exocentric directions presented a discontinuous pattern of overestimation of smaller angles that were subtended by radial orientations and accuracy of right angles that were subtended by horizontal orientations. This could be explained by the anisotropy of visual space, a well-established phenomenon from visual space studies. The analysis of the association between the processing of these two variables revealed independence between them in which exocentric direction processing did not depend on the processing of egocentric direction processing, and vice versa. The present results and prior evidence converge on the notion of hierarchical processing in which the visual system processes the egocentric distance of objects followed by exocentric distance processing and subsequent processing. The precise positions of egocentric and exocentric directions in this chain of processing remain to be determined.

Independence of egocentric and exocentric direction processing in visual space

One major issue concerning investigations of visual perception is determination of the geometrical properties of visual space. To address this issue, one must determine the relationships between geometrical features of visual space, distance, direction, angle, and size. Consistent evidence indicates that visual angle is a determinant of perceived exocentric distance. Previous evidence suggests that exocentric distance and direction are hierarchically processed, with distance preceding direction. The present study investigated the relationship between the perceptual processing of egocentric direction and exocentric direction using a task that independently provides both perceptual variables in a single judgment. The results indicated that egocentric directions were systematically overestimated, and this was not caused by either the global shape of the layout or leg length effects. Exocentric directions presented a discontinuous pattern of overestimation of smaller angles that were subtended by radial orientations and accuracy of right angles that were subtended by horizontal orientations. This could be explained by the anisotropy of visual space, a well-established phenomenon from visual space studies. The analysis of the association between the processing of these two variables revealed independence between them in which exocentric direction processing did not depend on the processing of egocentric direction processing, and vice versa. The present results and prior evidence converge on the notion of hierarchical processing in which the visual system processes the egocentric distance of objects followed by exocentric distance processing and subsequent processing. The precise positions of egocentric and exocentric directions in this chain of processing remain to be determined.(AU)