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Possible Involvement of Peripheral TRP Channels in the Hydrogen Roa‑Coria et al. BMC Neurosci (2019) 20:1 https://doi.org/10.1186/s12868-018-0483-3 BMC Neuroscience RESEARCH ARTICLE Open Access Possible involvement of peripheral TRP channels in the hydrogen sulfde‑induced hyperalgesia in diabetic rats José Eduardo Roa‑Coria1, Jorge Baruch Pineda‑Farias2, Paulino Barragán‑Iglesias2, Geovanna Nallely Quiñonez‑Bastidas1, Ángel Zúñiga‑Romero1, Juan Carlos Huerta‑Cruz3, Juan Gerardo Reyes‑García1, Francisco Javier Flores‑Murrieta1,3, Vinicio Granados‑Soto2 and Héctor Isaac Rocha‑González1* Abstract Background: Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfde ­(H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which ­H2S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in ­H2S-induced hyperalgesia in diabetic rats. Results: Streptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exog‑ enous donor of ­H2S, 3–100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3–3 µg/ paw), HC-030031 (100–316 µg/paw) and SKF-96365 (10–30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3–30 µg/paw), HC-030031 (100–1000 µg/paw) and SKF-96365 (10–100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced finching behavior. Hypergly‑ cemia, at 21 days, also increased protein expression of cystathionine-β-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expres‑ sion, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-in‑ duced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons. Conclusions: Our data suggest that ­H2S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fbers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy. Keywords: Cystathionine-β-synthase, Hydrogen sulfde, Hyperalgesia, Painful diabetic peripheral neuropathy, Streptozotocin-induced diabetes, Transient receptor potential channels *Correspondence: [email protected] 1 Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Miguel Hidalgo, 11340 Ciudad de México, Mexico Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Roa‑Coria et al. BMC Neurosci (2019) 20:1 Page 2 of 17 Background lacking CSE in sensory neurons has a pain threshold sim- Diabetes is a chronic disease that occurs when the pan- ilar to wild type mice, suggesting the existence of a com- creas does not produce enough insulin or when the body pensatory mechanism by other H2S-producing enzymes cannot efectively use insulin, leading to raised glucose [15]. levels in the blood. In North America and Caribbean In this regard, Wang and colleagues reported that CBS region there were 45.9 million of people with diabetes and P2X3, but not CSE, were up-regulated in a model of in 2017, and it has been estimated that there will be 62.2 lumbar disc herniation. Moreover, the systemic admin- million of people with diabetes in 2045 [1]. Te long-term istration of a CBS inhibitor reversed the over-expression hyperglycemia is associated with damage to the body and and function of P2X3 receptors, indicating the CBS- failure of various organs and tissues. Diabetic peripheral H2S-P2X3 signaling participates in the lumbar disc her- neuropathy is the most common and debilitating compli- niation-induced hypersensitivity [16]. Similarly, it has cation of diabetes, which is characterized by symptoms been suggested that CBS-H2S pathway participates in the of peripheral nerve dysfunction as hyperalgesia and allo- chronic constriction injury-induced allodynia through dynia [2]. Te treatment for painful diabetic peripheral the activation of NF-κβ(p65), ERK1/2 and CREB path- neuropathy includes glycemic control and symptomatic ways [17]. pain management. Food and Drug Administration has Our previous study suggests that H2S is involved in approved only duloxetine, pregabalin and tapentadol for diabetes-induced hyperalgesia and allodynia. However, the treatment of painful diabetic neuropathy, but they the molecular targets through which H2S induces pain- have low efcacy and are able to cause serious side efects ful disorders in diabetic neuropathy remains unclear [18]. [3, 4]. Te lack of an adequate pharmacological treat- It has been postulated that H 2S could modify the activity ment supports the need to clarify better the diabetes- of transient receptor potential (TRP) channels [19]. TRP associated painful peripheral neuropathy pathogenesis to channels are cation channels permeable to both mono- relieve this complication. valent and divalent cations as Na+ or Ca2+. Tey are Hydrogen sulfde (H 2S), a gasotransmitter, is mainly expressed in sensory neurons [20, 21] and are involved synthesized from l-cysteine by cystathionin-β-synthase in the modulation of diabetes-induced painful periph- (CBS), cystathionin-γ-lyase (CSE) and 3-mercaptopyru- eral neuropathy [22–24]. In addition, there is evidence vate sulfurtransferase in mammals [5, 6]. At physiologi- that H2S activates TRPA1 and TRPV1 channels to pro- cal concentrations, H2S appears to have a cytoprotective duce visceral pain [25, 26]. Based on the above considera- efect. However, its excessive production seems to con- tions, the current study was undertaken to investigate the tribute to the pathogenesis of painful disorders, septic possible participation of peripheral TRPV1, TRPA1 and shock and cerebral stroke, among others [7, 8]. TRPC channels in H2S-induced hyperalgesia in diabetic Most of literature indicates that H 2S has a pronocic- rats. eptive efect in somatic, visceral and neuropathic pain processing [9], although there is evidence suggesting an Results Streptozotocin‑induced hyperglycemia and increased antinociceptive role of H 2S in neuropathic pain [10]. In one of the neuropathic pain studies, authors reported that nociceptive behavior in the formalin test the administration of CSE inhibitors decreased hyperal- Intraperitoneal injection of streptozotocin, but not vehi- gesia and allodynia evoked by the right L5 spinal nerve cle, produced hyperglycemia in non-fasted rats after transection in rats [11]. In addition, intraplantar applica- 21 days. Te blood glucose level measured in these rats tion of NaHS (a donor of H2S) leads to hyperalgesia in was 85.3 ± 5.3 mg/dL and 81.7 ± 3.2 mg/dL before vehi- sham-operated rats, but not in rats subjected to genetic cle or streptozotocin injection and 79.2 ± 7.1 mg/dL and 2+ silencing of CaV3.2 T-type Ca channels, indicating that 398.9 ± 8.5 mg/dL 3 weeks after vehicle or streptozotocin CSE-derived endogenous H2S contributes to the mainte- injection, respectively. In addition, hyperglycemic rats nance of neuropathic pain through activation of Ca V3.2 showed polyphagia, polydipsia, polyuria and body weight T-type Ca2+ channels. In line with above results, the loss (data not shown). Formalin injection at 0.5% in nor- 2+ CSE-H2S-CaV3.2 T-type Ca channels pathway is sug- moglycemic and diabetic rats induced a typical biphasic gested to mediate the paclitaxel-induced neuropathic paw finching behavior. First phase began immediately hyperalgesia [12]. In fact, it has been demonstrated that after formalin administration and had a duration of about there are redox sites in the T-type Ca 2+ channels where 10 min. Second phase started about 15 min after formalin H2S may be exerting its peripheral sensitization efect on administration, had a maximum between 20 and 25 min, nociceptors [13, 14]. A recent study shows that periph- and lasted about 45 min (Fig. 1a). Diabetic rats displayed eral nerve injury increases CSE expression in dorsal root a greater finching behavior compared to normogly- ganglia (DRG). Furthermore, conditional knockout mice cemic rats during the second phase, but not in the frst Roa‑Coria et al. BMC Neurosci (2019) 20:1 Page 3 of 17 phase, after 14 and 21 days of the streptozotocin injection (Fig. 1b, c). Efect of H2S on formalin‑induced nociception in diabetic rats Ipsilateral peripheral pre-treatment (− 10 min) with NaHS (100 µg/paw) signifcantly (P < 0.05) increased 0.5% formalin-induced finching behavior during the second phase (Fig. 1a–c), but not during the frst phase (Fig. 1a, b), in diabetic rats. NaHS-induced hyperalgesia reached its maximum efect 3 weeks after streptozotocin injection in the 0.5% formalin test (Fig. 1a–c). In addition, NaHS (3–100 µg/paw) enhanced in a dose-dependent manner formalin-induced finching behavior (P < 0.05) during the second phase (Fig.
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