Intra-articular injection of 2-pyridylethylamine produces spinal NPY-mediated antinociception in the formalin-induced rat knee-joint pain model.

Low doses of histamine or H1R agonist 2-pyridylethylamine (2-PEA) into the knee-joint were found to decrease formalin-induced articular nociception in rats. In this study, we evaluated the participation of spinal NPY in the antinociceptive effect produced by 2-PEA. Injection of formalin (1.5%) into one of the knee-joints causes the limping of the respective limb due to nociception, which was registered each 5 min over 60 min. Neuropeptide Y1 receptor (Y1R) content in the spinal cord was evaluated by western-blotting. Intrathecal (i.t.) injection of Y1R agonist Leu31, Pro34-NPY (0.7-7 µmol) decreased nociception, while injection of the antagonist BIBO 3304 (4 µmol), increased nociception. Antinociception produced by 2-PEA was reversed by a sub-effective i.t. dose of the Y1R antagonist. Similarly, this antinociceptive effect was prevented by i.t. pretreatment with the neurotoxin NPY-saporin (750 ng), which also reduced immunoblotting for Y1R in spinal cord homogenates. These data support the idea that antinociception induced by H1R agonists in the knee-joint of rats may be mediated by the spinal release of NPY, and this peptide seems to be acting via Y1R.

An evolutionary recent IFN/IL-6/CEBP axis is linked to monocyte expansion and tuberculosis severity in humans.

Monocyte counts are increased during human tuberculosis (TB) but it has not been determined whether Mycobacterium tuberculosis (Mtb) directly regulates myeloid commitment. We demonstrated that exposure to Mtb directs primary human CD34+ cells to differentiate into monocytes/macrophages. In vitro myeloid conversion did not require type I or type II IFN signaling. In contrast, Mtb enhanced IL-6 responses by CD34+ cell cultures and IL-6R neutralization inhibited myeloid differentiation and decreased mycobacterial growth in vitro. Integrated systems biology analysis of transcriptomic, proteomic and genomic data of large data sets of healthy controls and TB patients established the existence of a myeloid IL-6/IL6R/CEBP gene module associated with disease severity. Furthermore, genetic and functional analysis revealed the IL6/IL6R/CEBP gene module has undergone recent evolutionary selection, including Neanderthal introgression and human pathogen adaptation, connected to systemic monocyte counts. These results suggest Mtb co-opts an evolutionary recent IFN-IL6-CEBP feed-forward loop, increasing myeloid differentiation linked to severe TB in humans.

Analgesic and anti-edematogenic effects of oral trypsin were abolished after subdiaphragmatic vagotomy and spinal monoaminergic inhibition in rats.

AIMS: Rheumatoid arthritis brings great burdens to the patients. In addition to the highly expensive treatment, they are commonly associated with severe side effects. In such context, the research for safe and affordable treatments is needed. MAIN METHODS: Arthritis was induced by CFA (0.5mg/mL) in female wistar rats. Trypsin was given p.o. (2.95mg/kg; 2mL) 24h after the intra-articular CFA injection. Articular incapacitation was measured daily by counting the paw elevation time (PET; s) during 1-min periods of stimulated walk, throughout the 7-days after intra-articular CFA injection. Articular diameter (AD) was accessed just after each PET measurement, taken the difference between naïve and diseased knee-joint diameter (cm). KEY FINDINGS: The present study showed that orally administered trypsin was able to reduce nociception and edema, effects that could be observed throughout the evaluation period. These effect, however, were not observed in animals underwent subdiaphragmatic vagotomy, suggesting a vagal mediation for trypsin effects. Likewise, these effects were blocked in rats which received intrathecal injection of the neurotoxins 5,7-dihydroxytryptamine or 6-hydroxydopamine, suggesting the involvement of spinal amines from axon terminals. SIGNIFICANCE: The present study proposes that oral trypsin may cause vagal activation, followed by the activation of descending inhibitory pathways and such mechanism may lead to a novel approach for the treatment of arthritis.

Histaminergic Pharmacology Modulates the Analgesic and Antiedematogenic Effects of Spinally Injected Morphine.

BACKGROUND: Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine. METHODS: After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group. RESULTS: Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect. CONCLUSIONS: Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.