Chronic pain is associated with the development of affective disorders but the underlying mechanisms are not fully understood. Changes in brain centres implicated in both emotional and pain processing are likely to be critical in the interplay of pain control and affective emotional behaviour. In the present study, we assessed emotional behaviour and performed a structural analysis of the amygdala (AMY) in neuropathic rats after two months of hyperalgesia and allodynia, induced by the spared nerve injury model (SNI). When compared with Sham-controls, SNI animals displayed signs of depressive-like behaviour. In addition, we found an increased amygdalar volume in SNI rats. No alterations were found in the dendritic arborizations of AMY neurons but, surprisingly, the amygdalar hypertrophy was associated with an increased cell proliferation [bromodeoxyuridine (BrdU)-positive cells] in the central (CeA) and basolateral (BLA) amygdaloid nuclei. The phenotypic analysis of the newly-acquired cells revealed that they co-label for neuronal markers (BrdU+NeuN and BrdU+Calbindin), but not for differentiated glial cells (BrdU+glial fibrillary acidic protein). We demonstrate that neuropathic pain promotes generation of new neurons in the AMY. Given the established role of the AMY in emotional behaviour, we propose that these neuroplastic changes might contribute for the development of depressive-like symptoms that are usually present in prolonged pain syndromes in humans.
Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (μ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.
Neuropathic pain (NP) often presents with comorbidities, including depression and anxiety. The amygdala is involved in the processing of mood disorders, fear, and the emotional-affective components of pain. Hemispheric lateralization of pain processing in the amygdala has recently been brought to light because, independently of the side of the peripheral injury, the right central nucleus of the amygdala (CeA) showed higher neuronal activity than the left in models of inflammatory pain. Although the CeA has been called the 'nociceptive amygdala', because of its high content of nociceptive neurones, little is known about changes in its neuronal function in vivo, under NP conditions. Herein, we quantified CeA spontaneous and evoked activity in rats subjected to spinal nerve ligation (SNL), under isoflurane anaesthesia, following application of mechanical and thermal stimuli to widespread body areas. We found that spontaneous and stimulus-evoked neuronal activity was higher in the left CeA at 2 and 6 days after SNL induction and declined afterwards, whereas activity in the right CeA became dominant at 14 days after surgery, independently of the side of surgery. We also observed that systemic injection of pregabalin, which is widely used in patients with NP, reduced CeA spontaneous and stimulus-evoked neuronal activity. Overall, we observed that peripheral nerve injury produced asymmetric plasticity in ongoing and evoked activity in the left and right CeA. Remarkably, at 14 days after SNL induction, enhanced evoked activity in the right CeA persisted compared to short-term increases in activity in the left CeA. The plasticity found in ongoing and evoked activity was inhibited by pregabalin.
The gene encoding cytochrome c nitrite reductase (NrfA) from Desulfovibrio desulfuricans ATCC 27774 was sequenced and the crystal structure of the enzyme was determined to 2.3-A resolution. In comparison with homologous structures, it presents structural differences mainly located at the regions surrounding the putative substrate inlet and product outlet, and includes a well defined second calcium site with octahedral geometry, coordinated to propionates of hemes 3 and 4, and caged by a loop non-existent in the previous structures. The highly negative electrostatic potential in the environment around hemes 3 and 4 suggests that the main role of this calcium ion may not be electrostatic but structural, namely in the stabilization of the conformation of the additional loop that cages it and influences the solvent accessibility of heme 4. The NrfA active site is similar to that of peroxidases with a nearby calcium site at the heme distal side nearly in the same location as occurs in the class II and class III peroxidases. This fact suggests that the calcium ion at the distal side of the active site in the NrfA enzymes may have a similar physiological role to that reported for the peroxidases.
Background Following neuropathy α2‐adrenoceptor‐mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5‐HT7 receptor densities are increased. Here, we manipulate spinal 5‐HT content in spinal nerve ligated (SNL) animals and investigate which 5‐HT receptor mediated actions predominate. Methods Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane‐anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5‐HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. Results DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. Conclusions We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5‐HT (presumed present following application of SSRI) were mediated via 5‐HT7 receptors. The anti‐nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2‐adrenoceptor. Significance Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5‐HT receptor‐mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.
In the past several years researchers have focused on the study of the antioxidant properties of barley and barley malt as well as their influence on beer quality. Some malt constituents have been reported as potent antioxidants due to their radical-scavenging and reducing properties, with a positive effect on beer oxidative stability. However, barley and malt can suffer some serious modifications during malting and roasting, namely on the levels of phenolic compounds and the development of Maillard reaction products, which may have a great impact on the overall antioxidant properties of malt. Although some studies have reported an increase of the antioxidant capacity during malting, others have mentioned an opposite effect. Recently, researchers have shown that compounds developed in malt during heat treatment at high temperature and long periods of time, as result of the Maillard reaction, can also exhibit pro-oxidant properties involving the metal-catalyzed Fenton reaction due to its reductive properties. This paper reviews important information and recent data regarding the chemical changes malting and roasting undergo along with their influence on the different antiand pro-oxidant properties described for barley and malt. The contribution of individual components to the overall antioxidant capacity of malt is also discussed.
The cytochrome c nitrite reductase is isolated from the membranes of the sulfate‐reducing bacterium Desulfovibrio desulfuricans ATCC 27774 as a heterooligomeric complex composed by two subunits (61 kDa and 19 kDa) containing c‐type hemes, encoded by the genes nrfA and nrfH, respectively. The extracted complex has in average a 2NrfA:1NrfH composition. The separation of ccNiR subunits from one another is accomplished by gel filtration chromatography in the presence of SDS. The amino‐acid sequence and biochemical subunits characterization show that NrfA contains five hemes and NrfH four hemes. These considerations enabled the revision of a vast amount of existing spectroscopic data on the NrfHA complex that was not originally well interpreted due to the lack of knowledge on the heme content and the oligomeric enzyme status. Based on EPR and Mössbauer parameters and their correlation to structural information recently obtained from X‐ray crystallography on the NrfA structure [Cunha, C.A., Macieira, S., Dias, J.M., Almeida, M.G., Gonçalves, L.M.L., Costa, C., Lampreia, J., Huber, R., Moura, J.J.G., Moura, I. & Romão, M. (2003) J. Biol. Chem. 278, 17455–17465], we propose the full assignment of midpoint reduction potentials values to the individual hemes. NrfA contains the high‐spin catalytic site (−80 mV) as well as a quite unusual high reduction potential (+150 mV)/low‐spin bis‐His coordinated heme, considered to be the site where electrons enter. In addition, the reassessment of the spectroscopic data allowed the first partial spectroscopic characterization of the NrfH subunit. The four NrfH hemes are all in a low‐spin state (S = 1/2). One of them has a gmax at 3.55, characteristic of bis‐histidinyl iron ligands in a noncoplanar arrangement, and has a positive reduction potential.
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