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Dive into the research topics where Sergi Leánez is active.

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Featured researches published by Sergi Leánez.


Journal of Pharmacology and Experimental Therapeutics | 2010

The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice

Arnau Hervera; Roger Negrete; Sergi Leánez; Jesús M. Martín-Campos; Olga Pol

Both δ-opioid receptor (DOPr) and cannabinoid-2 receptor (CB2R) agonists attenuate neuropathic pain, but the precise mechanism implicated in these effects is not completely elucidated. We investigated whether nitric oxide synthesized by neuronal (NOS1) or inducible (NOS2) nitric-oxide synthases could modulate DOPr and/or CB2R antiallodynic and antihyperalgesic effects through the peripheral nitric oxide-cGMP-protein kinase G (PKG) pathway activation and affect their expression during neuropathic pain. In wild-type (WT) mice at 21 days after chronic constriction of sciatic nerve, we evaluated the effects of [d-Pen2,d-Pen5]-enkephalin (DPDPE); (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH-015); and a NOS1 [N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N′-nitroguanidine tris(trifluoroacetate) salt; NANT], NOS2 [l-N(6)-(1-iminoethyl)-lysine; l-NIL], l-guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ], or PKG [(Rp)-8-(para-chlorophenylthio)guanosine-3′,5′-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs] inhibitor administered alone or combined. Expression of DOPr and CB2R mRNA in the spinal cord and dorsal root ganglia of naive and nerve-injured WT, NOS1-knockout (KO), and NOS2-KO mice, also was assessed. The subplantar administration of NANT, l-NIL, ODQ, or Rp-8-pCPT-cGMPs dose-dependently inhibited neuropathic pain and enhanced the local effects of DPDPE or JWH-015. Moreover, although the basal levels of DOPr and CB2R mRNA were similar between WT and NOS-KO animals, nerve injury only decreased (DOPr) or increased (CB2R) their expression in the dorsal root ganglia of WT and NOS2-KO mice, and not in NOS1-KO mice. Results suggest that inactivation of the nitric oxide-cGMP-PKG peripheral pathway triggered by NOS1 and NOS2 enhanced the peripheral actions of DOPr and CB2R agonists and that nitric oxide synthesized by NOS1 is implicated in the peripheral regulation of DOPr and CB2R gene transcription during neuropathic pain.


PLOS ONE | 2012

Carbon Monoxide Reduces Neuropathic Pain and Spinal Microglial Activation by Inhibiting Nitric Oxide Synthesis in Mice

Arnau Hervera; Sergi Leánez; Roger Negrete; Roberto Motterlini; Olga Pol

Background Carbon monoxide (CO) synthesized by heme oxygenase 1 (HO-1) exerts antinociceptive effects during inflammation but its role during neuropathic pain remains unknown. Our objective is to investigate the exact contribution of CO derived from HO-1 in the modulation of neuropathic pain and the mechanisms implicated. Methodology/Principal Findings We evaluated the antiallodynic and antihyperalgesic effects of CO following sciatic nerve injury in wild type (WT) or inducible nitric oxide synthase knockout (NOS2-KO) mice using two carbon monoxide-releasing molecules (CORM-2 and CORM-3) and an HO-1 inducer (cobalt protoporphyrin IX, CoPP) daily administered from days 10 to 20 after injury. The effects of CORM-2 and CoPP on the expression of HO-1, heme oxygenase 2 (HO-2), neuronal nitric oxide synthase (NOS1) and NOS2 as well as a microglial marker (CD11b/c) were also assessed at day 20 after surgery in WT and NOS2-KO mice. In WT mice, the main neuropathic pain symptoms induced by nerve injury were significantly reduced in a time-dependent manner by treatment with CO-RMs or CoPP. Both CORM-2 and CoPP treatments increased HO-1 expression in WT mice, but only CoPP stimulated HO-1 in NOS2-KO animals. The increased expression of HO-2 induced by nerve injury in WT, but not in NOS2-KO mice, remains unaltered by CORM-2 or CoPP treatments. In contrast, the over-expression of CD11b/c, NOS1 and NOS2 induced by nerve injury in WT, but not in NOS2-KO mice, were significantly decreased by both CORM-2 and CoPP treatments. These data indicate that CO alleviates neuropathic pain through the reduction of spinal microglial activation and NOS1/NOS2 over-expression. Conclusions/Significance This study reports that an interaction between the CO and nitric oxide (NO) systems is taking place following sciatic nerve injury and reveals that increasing the exogenous (CO-RMs) or endogenous (CoPP) production of CO may represent a novel strategy for the treatment of neuropathic pain.


PLOS ONE | 2010

The Spinal Cord Expression of Neuronal and Inducible Nitric Oxide Synthases and Their Contribution in the Maintenance of Neuropathic Pain in Mice

Arnau Hervera; Roger Negrete; Sergi Leánez; Jesús M. Martín-Campos; Olga Pol

Background Nitric oxide generated by neuronal (NOS1), inducible (NOS2) or endothelial (NOS3) nitric oxide synthases contributes to pain processing, but the exact role of NOS1 and NOS2 in the maintenance of chronic peripheral neuropathic pain as well as the possible compensatory changes in their expression in the spinal cord of wild type (WT) and NOS knockout (KO) mice at 21 days after total sciatic nerve ligation remains unknown. Methodology/Principal Findings The mechanical and thermal allodynia as well as thermal hyperalgesia induced by sciatic nerve injury was evaluated in WT, NOS1-KO and NOS2-KO mice from 1 to 21 days after surgery. The mRNA and protein levels of NOS1, NOS2 and NOS3 in the spinal cord of WT and KO mice, at 21 days after surgery, were also assessed. Sciatic nerve injury led to a neuropathic syndrome in WT mice, in contrast to the abolished mechanical allodynia and thermal hyperalgesia as well as the decreased or suppressed thermal allodynia observed in NOS1-KO and NOS2-KO animals, respectively. Sciatic nerve injury also increases the spinal cord expression of NOS1 and NOS2 isoforms, but not of NOS3, in WT and NOS1-KO mice respectively. Moreover, the presence of NOS2 is required to increase the spinal cord expression of NOS1 whereas an increased NOS1 expression might avoid the up-regulation of NOS2 in the spinal cord of nerve injured WT mice. Conclusions/Significance These data suggest that the increased spinal cord expression of NOS1, regulated by NOS2, might be responsible for the maintenance of chronic peripheral neuropathic pain in mice and propose these enzymes as interesting therapeutic targets for their treatment.


Anesthesiology | 2013

Treatment with Carbon Monoxide-releasing Molecules and an Ho-1 Inducer Enhances the Effects and Expression of µ-opioid Receptors during Neuropathic Pain

Arnau Hervera; Sergi Leánez; Roberto Motterlini; Olga Pol

Background:The administration of µ-opioid receptors (MOR) and &dgr;-opioid receptors (DOR) as well as cannabinoid-2 receptor (CB2R) agonists attenuates neuropathic pain. We investigated if treatment with two carbon monoxide-releasing molecules (CORM-2 and CORM-3) or an inducible heme oxygenase inducer (cobalt protoporphyrin IX, CoPP) could modulate the local and systemic effects and expression of MOR, DOR, and CB2R during neuropathic pain. Methods:In C57BL/6 mice, at 10 days after the chronic constriction of sciatic nerve, we evaluated the effects of the intraperitoneal administration of 10 mg/kg of CORM-2, CORM-3, or CoPP on the antiallodynic and antihyperalgesic actions of a locally or systemically administered MOR (morphine), DOR ([d-Pen(2),d-Pen(5)]-enkephalin) or CB2R ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone ) agonist. The effects of CORM-2 and CoPP treatments on the expression of MOR, DOR, CB2R, inducible and constitutive heme oxygenases, microglia activation marker (CD11b/c), and neuronal and inducible nitric oxide synthases were also assessed. Results:Treatments with CO-RMs and CoPP reduced the mechanical and thermal hypersensitivity induced by sciatic nerve injury, increased the local, but not systemic, antinociceptive effects of morphine, and decreased those produced by DPDPE and JWH-015. Both CORM-2 and CoPP treatments enhanced MOR and inducible heme oxygenase expression, unaltered DOR and constitutive heme oxygenase expression, and decreased the overexpression of CB2R, CD11b/c, and neuronal and inducible nitric oxide synthases induced by sciatic nerve injury. Conclusions:This study shows that CO-RMs and CoPP treatments increase the local antinociceptive effects of morphine through enhancing MOR peripheral expression and inhibiting spinal microglial activation and overexpression of neuronal/inducible nitric oxide synthases.


European Journal of Pharmacology | 2009

Peripheral antinociceptive effects of µ- and δ-opioid receptor agonists in NOS2 and NOS1 knockout mice during chronic inflammatory pain

Sergi Leánez; Arnau Hervera; Olga Pol

The aim of this study is to investigate the involvement of nitric oxide synthesized by the inducible (NOS2) or neuronal (NOS1) nitric oxide synthases in the local antinociceptive effects produced by micro- and delta-opioid receptor agonists during chronic inflammatory pain. Peripheral inflammatory pain was induced in NOS2 and NOS1 knockout mice and their wild type littermates by the subplantar administration of complete Freunds adjuvant (30 microl). The presence of paw inflammation, mechanical allodynia and thermal hyperalgesia induced by complete Freunds adjuvant were assessed by measuring paw diameter and using the von Frey filaments and plantar tests, respectively. During chronic inflammation, NOS2 deficient mice have a more rapid recovery of paw edema and a reduced thermal hyperalgesia compared to wild type. In contrast, a reduced paw edema and mechanical allodynia, as well as a modest rapid recovery from thermal hyperalgesia were observed in NOS1 knockout mice compared to wild type. The thermal hyperalgesia induced by complete Freunds adjuvant was not completely reversed by the subplantar administration of morphine (days 4 and 7) or [D-Pen (2,5)] enkephalin (DPDPE) (days 1 and 4) in NOS2 knockout mice as occurs in wild type mice. Moreover, the local administration of morphine or DPDPE also failed to reverse the decrease of ipsilateral paw withdrawal latency induced by complete Freunds adjuvant in NOS1 knockout mice throughout 10 days of peripheral inflammation. These results indicate the different roles played by nitric oxide synthesized by NOS2 or NOS1 in the maintenance of mechanical allodynia and thermal hyperalgesia induced by chronic inflammatory pain as well as, in the antinociceptive effects produced by micro- and delta-opioid receptor agonists during peripheral inflammatory pain.


Psychopharmacology | 2013

Effects of treatment with a carbon monoxide-releasing molecule and a heme oxygenase 1 inducer in the antinociceptive effects of morphine in different models of acute and chronic pain in mice

Arnau Hervera; Gemma Gou; Sergi Leánez; Olga Pol

RationaleTreatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer, CORM-2) or a classical heme oxygenase 1 inducer (cobalt protoporphyrin IX, CoPP) has potent anti-inflammatory effects, but the role played by these treatments in the antinociceptive effects of morphine during acute and chronic pain was not evaluated.ObjectivesIn wild type (WT), neuronal (NOS1-KO), or inducible (NOS2-KO) nitric oxide synthases knockout mice, we evaluated the effects of CORM-2 and CoPP treatments in the antinociceptive actions of morphine and their interaction with nitric oxide during acute, visceral, and chronic inflammatory or neuropathic pain.MethodsAcute and visceral pain was assessed through formalin and acid acetic writhing tests. Chronic inflammatory pain induced by the intra-articular administration of complete Freund’s adjuvant and neuropathic pain by partial ligation of sciatic nerve were evaluated by measuring allodynia and hyperalgesia using the von Frey filaments, plantar, or cold plate tests.ResultsWhile nitric oxide, synthetized by NOS1 and/or NOS2, increased the local antinociceptive effects of morphine during acute and chronic pain, it decreased the inhibitory effects of morphine after visceral pain. Moreover, while CORM-2 or CoPP treatments did not alter or reduced the antinociceptive effects of morphine during acute and visceral pain, both treatments improved the local antiallodynic and antihyperalgesic effects of morphine after chronic inflammatory or neuropathic pain in WT, but not in KO mice.ConclusionsCORM-2 and CoPP treatments improved the local antinociceptive effects of morphine during chronic inflammatory and neuropathic pain by interaction with nitric oxide synthetized by NOS1 and NOS2 isoforms.


Journal of Pharmacology and Experimental Therapeutics | 2014

Treatment with a Heme Oxygenase 1 Inducer Enhances the Antinociceptive Effects of µ-Opioid, δ-Opioid, and Cannabinoid 2 Receptors during Inflammatory Pain

Mireia Carcolé; Sílvia Castany; Sergi Leánez; Olga Pol

The administration of µ-opioid receptor (MOR), δ-opioid receptor (DOR), and cannabinoid 2 receptor (CB2R) agonists attenuates inflammatory pain. We investigated whether treatment with the heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the local effects and expression of MOR, DOR, or CB2R during chronic inflammatory pain. In mice with inflammatory pain induced by the subplantar administration of complete Freund’s adjuvant, we evaluated the effects of the intraperitoneal administration of 10 mg/kg CoPP on the antiallodynic and antihyperalgesic actions of locally administered MOR (morphine), DOR (DPDPE {[d-Pen(2),d-Pen(5)]-enkephalin}), or CB2R [JWH-015 {(2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone}] agonists and its reversion with the HO-1 inhibitor, tin protoporphyrin IX (SnPP). The effect of CoPP treatment on the dorsal root ganglia expression of HO-1, MOR, DOR, and CB2R was also assessed. The results show that treatment with CoPP increased the local antinociceptive effects produced by morphine, DPDPE, or JWH-015 during chronic inflammatory pain, and these effects were blocked by the subplantar administration of SnPP, indicating the participation of HO-1 in the antinociceptive actions. CoPP treatment, apart from inducing the expression of HO-1, also enhanced the expression of MOR, did not alter CB2R, and avoided the decreased expression of DOR induced by inflammatory pain. This study shows that the HO-1 inducer (CoPP) increased the local antinociceptive effects of MOR, DOR, and CB2R agonists during inflammatory pain by altering the peripheral expression of MOR and DOR. Therefore, the coadministration of CoPP with local morphine, DPDPE, or JWH-015 may be a good strategy for the management of chronic inflammatory pain.


PLOS ONE | 2011

The antinociceptive effects of JWH-015 in chronic inflammatory pain are produced by nitric oxide-cGMP-PKG-KATP pathway activation mediated by opioids.

Roger Negrete; Arnau Hervera; Sergi Leánez; Jesús M. Martín-Campos; Olga Pol

Background Cannabinoid 2 receptor (CB2R) agonists attenuate inflammatory pain but the precise mechanism implicated in these effects is not completely elucidated. We investigated if the peripheral nitric oxide-cGMP-protein kinase G (PKG)-ATP-sensitive K+ (KATP) channels signaling pathway triggered by the neuronal nitric oxide synthase (NOS1) and modulated by opioids, participates in the local antinociceptive effects produced by a CB2R agonist (JWH-015) during chronic inflammatory pain. Methodology/Principal Findings In wild type (WT) and NOS1 knockout (NOS1-KO) mice, at 10 days after the subplantar administration of complete Freunds adjuvant (CFA), we evaluated the antiallodynic (von Frey filaments) and antihyperalgesic (plantar test) effects produced by the subplantar administration of JWH-015 and the reversion of their effects by the local co-administration with CB2R (AM630), peripheral opioid receptor (naloxone methiodide, NX-ME) or CB1R (AM251) antagonists. Expression of CB2R and NOS1 as well as the antinociceptive effects produced by a high dose of JWH-015 combined with different doses of selective L-guanylate cyclase (ODQ) or PKG (Rp-8-pCPT-cGMPs) inhibitors or a KATP channel blocker (glibenclamide), were also assessed. Results show that the local administration of JWH-015 dose-dependently inhibited the mechanical and thermal hypersensitivity induced by CFA which effects were completely reversed by the local co-administration of AM630 or NX-ME, but not AM251. Inflammatory pain increased the paw expression of CB2R and the dorsal root ganglia transcription of NOS1. Moreover, the antinociceptive effects of JWH-015 were absent in NOS1-KO mice and diminished by their co-administration with ODQ, Rp-8-pCPT-cGMPs or glibenclamide. Conclusions/Significance These data indicate that the peripheral antinociceptive effects of JWH-015 during chronic inflammatory pain are mainly produced by the local activation of the nitric oxide-cGMP-PKG-KATP signaling pathway, triggered by NOS1 and mediated by endogenous opioids. These findings suggest that the activation of this pathway might be an interesting therapeutic target for the treatment of chronic inflammatory pain with cannabinoids.


PLOS ONE | 2016

The Induction of Heme Oxygenase 1 Decreases Painful Diabetic Neuropathy and Enhances the Antinociceptive Effects of Morphine in Diabetic Mice

Sílvia Castany; Mireia Carcolé; Sergi Leánez; Olga Pol

Painful diabetic neuropathy is a common complication of diabetes mellitus which is poorly controlled by conventional analgesics. This study investigates if treatment with an heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the allodynia and hyperalgesia induced by diabetes and enhanced the antinociceptive effects of morphine. In a diabetic mice model induced by the injection of streptozotocin (STZ), we evaluated the antiallodynic and antihyperalgesic effects produced by the intraperitoneal administration of 5 and 10 mg/kg of CoPP at several days after its administration. The antinociceptive actions produced by the systemic administration of morphine alone or combined with CoPP were also evaluated. In addition, the effects of CoPP treatment on the expression of HO-1, the microglial activation marker (CD11b/c), the inducible nitric oxide synthase (NOS2) and μ-opioid receptors (MOR), were also assessed. Our results showed that the administration of 10 mg/kg of CoPP during 5 consecutive days completely blocked the mechanical and thermal hypersensitivity induced by diabetes. These effects are accompanied by the increased spinal cord, dorsal root ganglia and sciatic nerve protein levels of HO-1. In addition, the STZ-induced activation of microglia and overexpression of NOS2 in the spinal cord were inhibited by CoPP treatment. Furthermore, the antinociceptive effects of morphine were enhanced by CoPP treatment and reversed by the administration of an HO-1 inhibitor, tin protoporphyrin IX (SnPP). The spinal cord expression of MOR was also increased by CoPP treatment in diabetic mice. In conclusion, our data provide the first evidence that the induction of HO-1 attenuated STZ-induced painful diabetic neuropathy and enhanced the antinociceptive effects of morphine via inhibition of microglia activation and NOS2 overexpression as well as by increasing the spinal cord levels of MOR. This study proposes the administration of CoPP alone or combined with morphine as an interesting therapeutic approach for the treatment of painful diabetic neuropathy.


Neuroscience Letters | 2016

The antinociceptive effects of a δ-opioid receptor agonist in mice with painful diabetic neuropathy: Involvement of heme oxygenase 1.

Sílvia Castany; Mireia Carcolé; Sergi Leánez; Olga Pol

Diabetic neuropathy is poorly controlled by classical analgesics and the research of new therapeutic alternatives is indispensable. Our aim is to investigate if treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer; CORM-2) or an inducible heme oxygenase (HO-1) inducer (cobalt protoporphyrin IX; CoPP) could enhance the antinociceptive effects produced by a δ-opioid receptor (DOR) agonist in mice with painful diabetic neuropathy. In diabetic mice induced by streptozotocin (STZ) injection, the antiallodynic and antihyperalgesic effects produced by the subcutaneous administration of a DOR agonist ([d-Pen(2),d-Pen(5)]-Enkephalin; DPDPE) and the reversion of its effects with the administration of an HO-1 inhibitor (tin protoporphyrin IX; SnPP) were evaluated. Moreover, the antinociceptive effects produced by the intraperitoneal administration of 10mg/kg of CORM-2 or CoPP, alone or combined, with a subanalgesic dose of DPDPE were also assessed. Our results demonstrated that the subcutaneous administration of DPDPE inhibited the mechanical and thermal allodynia as well as the thermal hyperalgesia induced by diabetes in a dose-dependent manner. Moreover, while the antinociceptive effects produced by a low dose of DPDPE were enhanced by CORM-2 or CoPP co-treatments, the inhibitory effects produced by a high dose of DPDPE were completely reversed by the administration of an HO-1 inhibitor, SnPP, indicating the involvement of HO-1 in the antinociceptive effects produced by this DOR agonist during diabetic neuropathic pain in mice. In conclusion, this study shows that the administration of CORM-2 or CoPP combined with a DOR agonist could be an interesting strategy for the treatment of painful diabetic neuropathy.

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Olga Pol

Autonomous University of Barcelona

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Arnau Hervera

Autonomous University of Barcelona

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Roger Negrete

Autonomous University of Barcelona

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Mireia Carcolé

Autonomous University of Barcelona

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Sílvia Castany

Autonomous University of Barcelona

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Alejandro Redondo

Autonomous University of Barcelona

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Christina McDonnell

Autonomous University of Barcelona

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Gabriela Riego

Autonomous University of Barcelona

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Gemma Gou

Autonomous University of Barcelona

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