Abstract:
:Hydrogen sulfide (H2S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial. The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H2S donors (the natural allyl-isothiocyanate and the synthetics phenyl- and carboxyphenyl-isothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity. The potential contribution of Kv7 potassium channels modulation was also studied. Mice were treated with paclitaxel (2.0 mg kg-1) i.p. on days 1, 3, 5 and 7; oxaliplatin (2.4 mg kg-1) was administered i.p. on days 1-2, 5-9, 12-14. Behavioral tests were performed on day 15. In both models, single subcutaneous administrations of H2S donors (1.33, 4.43, 13.31 μmol kg-1) reduced the hypersensitivity to cold non-noxious stimuli (allodynia-related measurement). The prototypical H2S donor NaHS was also effective. Activity was maintained after i.c.v. administrations. On the contrary, the S-lacking molecule allyl-isocyanate did not increase pain threshold; the H2S-binding molecule hemoglobin abolished the pain-relieving effects of isothiocyanates and NaHS. The anti-neuropathic properties of H2S donors were reverted by the Kv7 potassium channel blocker XE991. Currents carried by Kv7.2 homomers and Kv7.2/Kv7.3 heteromers expressed in CHO cells were potentiated by H2S donors. Sistemically- or centrally-administered isothiocyanates reduced chemotherapy-induced neuropathic pain by releasing H2S. Activation of Kv7 channels largely mediate the anti-neuropathic effect.
journal_name
Neuropharmacologyjournal_title
Neuropharmacologyauthors
Di Cesare Mannelli L,Lucarini E,Micheli L,Mosca I,Ambrosino P,Soldovieri MV,Martelli A,Testai L,Taglialatela M,Calderone V,Ghelardini Cdoi
10.1016/j.neuropharm.2017.04.029subject
Has Abstractpub_date
2017-07-15 00:00:00pages
49-59eissn
0028-3908issn
1873-7064pii
S0028-3908(17)30179-Xjournal_volume
121pub_type
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