Browsing by Author "Gadotti, Vinícius Maria"
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Item Open Access Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist(BioMed Central Ltd., 2013-07-01) You, Haitao; Gadotti, Vinícius Maria; Petrov, Ravil R.; Berger, N. Daniel; Diaz, Philippe J.; Zamponi, Gerald W.Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181.Item Open Access A cell-permeant peptide corresponding to the cUBP domain of USP5 reverses inflammatory and neuropathic pain(Sage Publishing, 2016-01-01) García-Caballero, Agustín; Gadotti, Vinícius Maria; Chen, Lina; Zamponi, Gerald W.Cav3.2 T-type calcium currents in primary afferents are enhanced in various painful pathological conditions, whereas inhibiting Cav3.2 activity or expression offers a strategy for combating the development of pain hypersensitivity. We have shown that Cav3.2 channel surface density is strongly regulated by the ubiquitination machinery and we identified the deubiquitinase USP5 as a Cav3.2 channel interacting protein and regulator of its cell surface expression. We also reported that USP5 is upregulated in chronic pain conditions. Conversely, preventing its binding to the channel in vivo mediates analgesia in inflammatory and neuropathic pain models.Item Open Access Cellular prion protein protects from inflammatory and neuropathic pain(BioMed Central Ltd., 2011-08-16) Gadotti, Vinícius Maria; Zamponi, Gerald W.Cellular prion protein (PrPC) inhibits N-Methyl-D-Aspartate (NMDA) receptors. Since NMDA receptors play an important role in the transmission of pain signals in the dorsal horn of spinal cord, we thus wanted to determine if PrPC null mice show a reduced threshold for various pain behaviours.We compared nociceptive thresholds between wild type and PrPC null mice in models of inflammatory and neuropathic pain, in the presence and the absence of a NMDA receptor antagonist. 2-3 months old male PrPC null mice exhibited an MK-801 sensitive decrease in the paw withdrawal threshold in response both mechanical and thermal stimuli. PrPC null mice also exhibited significantly longer licking/biting time during both the first and second phases of formalin-induced inflammation of the paw, which was again prevented by treatment of the mice with MK-801, and responded more strongly to glutamate injection into the paw. Compared to wild type animals, PrPC null mice also exhibited a significantly greater nociceptive response (licking/biting) after intrathecal injection of NMDA. Sciatic nerve ligation resulted in MK-801 sensitive neuropathic pain in wild-type mice, but did not further augment the basal increase in pain behaviour observed in the null mice, suggesting that mice lacking PrPC may already be in a state of tonic central sensitization. Altogether, our data indicate that PrPC exerts a critical role in modulating nociceptive transmission at the spinal cord level, and fit with the concept of NMDA receptor hyperfunction in the absence of PrPC.Item Open Access Depressive-like behaviour of mice lacking cellular prion protein(Elsevier, 2012-02) Bonfield, Stephan P.; Zamponi, Gerald W.; Gadotti, Vinícius MariaCellular Prion Protein (PrP(C)) is known to mediate a protective role in several neurological conditions such as ischemia and epilepsy. However, so far, little information is available concerning the role of PrP(C) in psychiatric disorders such as depression. Here, we have used PrP(C) null mice to examine a putative role of PrP(C) in depressive-like states. Prion protein null mice exhibited depressive-like behaviour when compared to wild-type mice in both the Forced Swimming Test (FST) and Tail Suspension Test (TST). The clinical antidepressant drug imipramine and the NMDA receptor antagonist MK-801 reversed the depressive-like behaviour observed for knockout mice in the TST. The present data thus indicate that PrP(C) exerts a critical role in modulating the depressive-like state in mice, reinforcing the notion that PrP(C) might be associated with alterations in mood disorder states, and suggests a possible role of PrP(C) as a potential drug target for treating depressive disorders.Item Open Access Small organic molecule disruptors of Cav3.2 - USP5 interactions reverse inflammatory and neuropathic pain(BioMed Central Ltd., 2015-12) Gadotti, Vinícius Maria; Caballero, Agustin Garcia; Berger, N. Daniel; Gladding, Clare M.; Chen, Lina; Pfeifer, Tom A.; Zamponi, Gerald W.Cav3.2 channels facilitate nociceptive transmission and are upregulated in DRG neurons in response to nerve injury or peripheral inflammation. We reported that this enhancement of Cav3.2 currents in afferent neurons is mediated by deubiquitination of the channels by the deubiquitinase USP5, and that disrupting USP5/Cav3.2 channel interactions protected from inflammatory and neuropathic pain.Item Open Access TMEM16C cuts pain no SLACK(Nature neuroscience, 2013-09-01) Gadotti, Vinícius Maria; Zamponi, Gerald W.TMEM16C has an unexpected role in regulating the activity and cell surface expression of sodium-activated potassium (SLACK) channels. By enhancing SLACK currents, TMEM16C indirectly inhibits pain signaling.