Search Results (3)

Growing evidence points to the histamine system as a promising target for the management of neuropathic pain. Preclinical studies reported the efficacy of H₃R antagonists in reducing pain hypersensitivity in models of neuropathic pain through an increase of histamine release within the CNS. Recently, a promising efficacy of H₄R agonists as anti-neuropathic agents has been postulated. Since H₃R and H₄R are both localized in neuronal areas devoted to pain processing, the aim of the study is to investigate the role of H₄R in the mechanism of anti-hyperalgesic action of the H₃R antagonist GSK189254 in the spared nerve injury (SNI) model in mice. Oral (6 mg/kg), intrathecal (6 µg/mouse), or intra locus coeruleus (LC) (10 µg/µL) administration of GSK189254 reversed mechanical and thermal allodynia in the ipsilateral side of SNI mice. This effect was completely prevented by pretreatment with the H₄R antagonist JNJ 10191584 (6 µg/mouse i.t.; (10 µg/µL intraLC). Furthermore, GSK189254 was devoid of any anti-hyperalgesic effect in H₄R deficient mice, compared with wild type mice. Conversely, pretreatment with JNJ 10191584 was not able to prevent the hypophagic activity of GSK189254. In conclusion, we demonstrated the selective contribution of H₄R to the H₃R antagonist-induced attenuation of hypernociceptive behavior in SNI mice. These results might help identify innovative therapeutic interventions for neuropathic pain. Full article

Neuropathic pain is a disease caused by structural and functional plasticity in central and peripheral sensory pathways that produce alterations in nociceptive processing. Currently, pharmacological treatment for this condition remains a challenge. Crotoxin (CTX), the main neurotoxin of Crotalus durissus terrificus rattlesnake venom, has well described prolonged anti-inflammatory and antinociceptive activities. In spite of its potential benefits, the toxicity of CTX remains a limiting factor for its use. SBA-15 is an inert nanostructured mesoporous silica that, when used as a vehicle, may reduce toxicity and potentiate the activity of different compounds. Based on this, we propose to conjugate crotoxin with SBA-15 (CTX:SBA-15) in order to investigate if when adsorbed to silica, CTX would have its toxicity reduced and its analgesic effect enhanced in neuropathic pain induced by the partial sciatic nerve ligation (PSNL) model. SBA-15 enabled an increase of 35% of CTX dosage. Treatment with CTX:SBA-15 induced a long-lasting reduction of mechanical hypernociception, without modifying the previously known pathways involved in antinociception. Moreover, CTX:SBA-15 reduced IL-6 and increased IL-10 levels in the spinal cord. Surprisingly, the antinociceptive effect of CTX:SBA-15 was also observed after oral administration. These data indicate the potential use of the CTX:SBA-15 complex for neuropathic pain control and corroborates the protective potential of SBA-15. Full article

Gedunin, a natural limonoid from Meliaceae species, has been previously described as an antiinflammatory compound in experimental models of allergic inflammation. Here, we report the antiinflammatory and antinociceptive effects of gedunin in an acute model of articular inflammation induced by zymosan (500 μg/cavity; intra-articular) in C57BL/6 mice. Intraperitoneal (i.p.) pretreatment with gedunin (0.005–5 mg/kg) impaired zymosan-induced edema formation, neutrophil accumulation and hypernociception in mouse knee joints, due to decreased expression of preproET-1 mRNA and production of LTB₄, PGE₂, TNF-α and IL-6. Mouse post-treatment with gedunin (0.05 mg/kg; i.p.) 1 and 6 h after stimulation also impaired articular inflammation, by reverting edema formation, neutrophil accumulation and the production of lipid mediators, cytokines and endothelin. In addition, gedunin directly modulated the functions of neutrophils and macrophages in vitro. The pre-incubation of neutrophil with gedunin (100 µM) impaired shape change, adhesion to endothelial cells, chemotaxis and lipid body formation triggered by different stimuli. Macrophage pretreatment with gedunin impaired intracellular calcium mobilization, nitric oxide production, inducible nitric oxide synthase expression and induced the expression of the antiinflammatory chaperone heat shock protein 70. Our results demonstrate that gedunin presents remarkable antiinflammatory and anti-nociceptive effects on zymosan-induced inflamed knee joints, modulating different cell populations. Full article