Lower antidepressant response to fluoxetine is associated with anxiety-like behavior, hippocampal oxidative imbalance, and increase on peripheral IL-17 and IFN-γ levels.

Major depression is a leading contributor to the global burden of disease. This is mainly related to the disorder chronic and recurrent nature, and to high rates of refractoriness to treatment. Limited efficacy with currently available antidepressants highlights the need for more effective options for treating drug-resistant patients and emphasizes the importance of developing specific preclinical models for treatment-resistant populations. Treatment-resistant depression (TRD) is commonly defined as failure to respond to two or more trials of antidepressants. In this study, we investigated the effect of fluoxetine treatment for fourteen days on the depressive-like behavior and the oxidative and inflammatory parameters of mice submitted to chronic corticosterone administration. After 21 days of subcutaneous corticosterone administration (20 mg/kg/day) and 14 days of oral fluoxetine treatment (10 mg/kg/day, started on day 7 of induction protocol), we separated animals into two groups according to the tail suspension test (TST) results: antidepressant responders (good response to antidepressant, GRA) and non-responders (resistance to antidepressant, AR). Forced swimming test (FST), elevated plus maze test (EPMT), and open field test (OFT) were performed. We found that animals classified as AR (i.e., those with higher immobility values in the TST) demonstrated anxiety-like behavior in the EPMT, increased H2O2 levels, and decreased catalase activity in the hippocampus, as well as increased serum levels of IL-17 and IFN-γ. Our findings suggest that a redox imbalance in the hippocampus, combined with increased levels of peripheral IL-17 and INF-γ, may be involved with an impaired response to fluoxetine.

Root bark of Discaria americana attenuates pain: A pharmacological evidence of interaction with opioidergic system and TRP/ASIC channels.

ETHNOPHARMACOLOGICAL RELEVANCE: Discaria americana (Rhamnaceae) root bark infusion have been used in traditional medicine as antipyretic, tonic, ameliorative of stomach and skin diseases and diabetes. This study was designed to investigate whether the methanolic extract of the root bark of Discaria americana (MEDa) exhibits antinociceptive effects in mice. Furthermore, it was investigated the involvement of the opioidergic system in MEDa mechanism of action as well the interactions with TRP/ASIC channels in its effect. MATERIALS AND METHODS: The antinociceptive effect of intra-gastric gavage (i.g.) of MEDa (0.3-300 mg/kg) was evaluated in mice subjected to acute chemical (acetic-acid, formalin, glutamate, capsaicin, cinnamaldehyde, and acidified saline) or thermal (hot plate) tests of pain. The involvement of opioid system was evaluated in the formalin test. A nonspecific effect of MEDa was observed by measuring locomotor activity and exploratory behavior in open field test. RESULTS: MEDa significantly reduced the number of writhing induced by acetic acid and inhibited the nociception in the two phases of formalin. These effects were inhibited by pretreatment with naloxone. The nociception induced by hot plate and intraplantar injection of glutamate, capsaicin, cinnamaldehyde and acidified saline were significantly inhibited by MEDa. Only the dose of 300 mg/kg altered the locomotor activity. CONCLUSIONS: Our results demonstrated, for the first time, that the methanolic extract of the root bark of Discaria americana presents antinociceptive effect in chemical and thermal stimuli and its analgesic properties can be due activation of the opioidergic system. These results support the use of Discaria americana in traditional medicine and demonstrate that this plant presents a therapeutic potential for the development of phytomedicines with antinociceptive profile.

Oral treatment with methanolic extract of the root bark of Condalia buxifolia Reissek alleviates acute pain and inflammation in mice: Potential interactions with PGE2, TRPV1/ASIC and PKA signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The Condalia buxifolia root bark infusion is used in traditional medicine in Brazil as antipyretic, anti-inflammatory and anti-dysentery. Previous data from our group showed that methanolic extract of Condalia buxifolia (MECb) produced a marked antinociceptive effect in animal models of acute pain. The purpose of this study was to investigate the mechanisms of MECb-induced antinociception as measured by nocifensive behavior in pain induced by endogenous (prostaglandin E2) or exogenous (TRPs and ASIC agonist, and protein kinase A and C activators) chemical stimuli, and the potential role of PKA signaling and capsaicin-sensitive central C-fiber afferents. MATERIALS AND METHODS: The effect of MECb administered orally (0.1-300mg/kg, i.g.) to mice on nociception induced by capsaicin (TRPV1 agonist), cinnamaldehyde (TRPA1 agonist), menthol (TRPM8 agonist), acidified saline (ASIC agonist), PMA (protein kinase C activator), PGE2 and forskolin (protein kinase A activator) was assessed. Moreover, this study also investigated the role of C-fibers desensitizing mice with a high dose of intrathecal capsaicin. Furthermore, this study performed the western blot to PKA phosphorylated on nocifensive behavior induced by forskolin. RESULTS: MECb was able to reduce the nociception and paw edema induced by capsaicin, acidified saline, PMA, PGE2 and forskolin, but not by cinnamaldehyde or menthol. Western blot analyses showed that MECb reduced the levels of PKA phosphorylation induced by forskolin in hind paws. Finally, ablating central afferent C-fibers abolished MECb antinociception. CONCLUSION: In accordance with its use in traditional medicine, these findings provide new evidence indicating that Condalia buxifolia reduces the acute painful behavior of animals caused by chemical stimuli. The precise mechanism of MECb antinociceptive activity is not completely understood but the results suggest involvement of PGE2, TRPV1/ASIC and PKA signaling pathways, and require integrity of the capsaicin-sensitive central C-fiber afferents.

Involvement of spinal neurokinins, excitatory amino acids, proinflammatory cytokines, nitric oxide and prostanoids in pain facilitation induced by Phoneutria nigriventer spider venom.

The major local symptom of Phoneutria nigriventer envenomation is an intense pain, which can be controlled by infiltration with local anesthetics or by systemic treatment with opioid analgesics. Previous work showed that intraplantar (i.pl) injection of Phoneutria nigriventer venom in rats induces hyperalgesia, mediated peripherally by tachykinin and glutamate receptors. The present study examined the spinal mechanisms involved in pain-enhancing effect of this venom. Intraplantar injection of venom into rat hind paw induced hyperalgesia. This phenomenon was inhibited by intrathecal (i.t.) injection of tachykinin NK1 (GR 82334) or NK2 (GR 94800) receptor antagonists, a calcitonin gene-related peptide (CGRP) receptor antagonist (CGRP8-37) and N-methyl-D-aspartate (NMDA; MK 801 and AP-5), non-NMDA ionotropic (CNQX), or metabotropic (AIDA and MPEP) glutamate receptor antagonists, suggesting the involvement of spinal neurokinins and excitatory amino acids. The role of proinflammatory cytokines, nitric oxide (NO), and prostanoids in spinally mediated pain facilitation was also investigated. Pharmacological blockade of tumour necrosis factor-alpha (TNFalpha) or interleukin-1beta (IL-1beta) reduced the hyperalgesic response to venom. Intrathecal injection of L-N6-(1-iminoethyl)lysine (L-NIL), but not of 7-nitroindazole (7-NI), inhibited hyperalgesia induced by the venom, indicating that NO, generated by the activity of the inducible form of nitric oxide synthase, also mediates this phenomenon. Furthermore, indomethacin, an inhibitor of cyclooxigenases (COX), or celecoxib, a selective inhibitor of COX-2, abolished venom-induced hyperalgesia, suggesting the involvement of spinal prostanoids in this effect. These data indicate that the spinal mechanisms of pain facilitation induced by Phoneutria nigriventer venom involves a plethora of mediators that may cooperate in the genesis of venom-induced central sensitization.

Peripheral tackykinin and excitatory amino acid receptors mediate hyperalgesia induced by Phoneutria nigriventer venom.

The generation of hyperalgesia by Phoneutria nigriventer venom was investigated in rats using the paw pressure test, through the intraplantar injection of the venom. Hyperalgesia was significantly inhibited by N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine), a vanilloid receptor antagonist, by the local administration of pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Pro (spiro-gamma-lactam) Leu-Trp-NH(2) (GR82334) or of Phenyl-CO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH(2) (GR94800), inhibitors of tachykinin NK(1) and NK(2) receptors, respectively, or by the local injection of dizocilpine (MK 801), (+/-)-2-amino-5-phosphonopentanoic acid ((+/-)-AP-5), or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and non-NMDA excitatory amino acid receptors. The correlation between hyperalgesia and the inflammatory response induced by the venom was also investigated. The venom-induced edematogenic response was not modified by the pharmacological treatments. These results suggest that hyperalgesia induced by P. nigriventer venom is mediated by stimulation of capsaicin-sensitive neurons, with activation of peripheral tachykinin NK(1) and NK(2) receptors and of both the NMDA and AMPA receptors. Distinct mechanisms are involved in the development of hyperalgesia and edema induced by the venom.

Peripheral tackykinin and excitatory amino acid receptors mediatehyperalgesia induced by Phoneutria nigriventer venom

Abstract The generation of hyperalgesia by Phoneutria nigriventer venom was investigated in rats using the paw pressure test, through the intraplantar injection of the venom. Hyperalgesia was significantly inhibited by N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine), a vanilloid receptor antagonist, by the local administration of pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Pro (spiro-ã-lactam) Leu-Trp-NH2 (GR82334) or of Phenyl-CO-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (GR94800), inhibitors of tachykinin NK1 and NK2 receptors, respectively, or by the local injection of dizocilpine (MK 801), (±)-2-amino-5-phosphonopentanoic acid ((±)-AP-5), or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), antagonists of NMDA and non-NMDA excitatory amino acid receptors. The correlation between hyperalgesia and the inflammatory response induced by the venom was also investigated. The venom-induced edematogenic response was not modified by the pharmacological treatments. These results suggest that hyperalgesia induced by P. nigriventer venom is mediated by stimulation of capsaicin-sensitive neurons, with activation of peripheral tachykinin NK1 and NK2 receptors and of both the NMDA and AMPA receptors. Distinct mechanisms are involved in the development of hyperalgesia and edema induced by the venom.