The antagonistic effect of the sigma 1 receptor ligand (+)-MR200 on persistent pain induced by inflammation.

OBJECTIVE AND DESIGN: The sigma 1 (σ1) receptor, which is widely distributed in the CNS in areas that are known to be important for pain control, may play a role in persistent pain characterized by the hypersensitivity of nociceptive transmission. Here, we investigated the effect of σ1 blockade in an inflammatory pain model. TREATMENT AND METHODS: An intraplantar injection of carrageenan (2 %) was used to induce paw inflammation. The effects of the σ1 antagonist (+)-MR200, given subcutaneously at a dose of 0.1, 0.25, 0.5,1, 1.5, and 2 mg/kg prior to injection of carrageenan, on inflammatory pain and inflammation were assessed. Mechanical allodynia with von Frey filaments, thermal hyperalgesia with the plantar test and edema evaluation with a plethysmometer were measured. Intergroup comparisons were assessed by one- or two-way analysis of variance when appropriate, followed by post-hoc tests (Dunnett's test for one-way or Bonferroni for two-way ANOVA). RESULTS: (+)-MR200 dose-dependently prevented allodynia and hyperalgesia induced by carrageenan. Furthermore, it reduced paw edema with a significant inhibition percentage of 37.82 % at 3 h after carrageenan treatment. CONCLUSIONS: The blockade of the σ1 receptor with the selective antagonist (+)-MR200 may contribute to the suppression of the typical symptoms of inflammatory pain.

Effects of a selective sigma 1 antagonist compound on inflammatory pain.

The compound (−)-MRV3 [(−)-Methyl (1S,2R)-2-[(4-Hydroxy-4-phenylpiperidin-1-yl)-methyl]-1-phenylcyclopropanecarboxylate] has an assessed antagonistsigma 1 (σ1) profile and showed improved σ1/σ2 selectivity with respect to the parent compound(+)-MR200. The σ1 receptor is reported to play arole in both central sensitization and pain hypersensitivity,which suggests a potential use of σ1 antagonists forthe treatment of persistent pain conditions. The present study was performed to assess the effects of theselective σ1 antagonist (−)-MRV3, in carrageenan-inducedinflammatory hyperalgesia, allodynia and edema.Mechanical allodynia with a series of calibratedvon Frey's filaments, thermal hyperalgesia with plantartest and edema evaluation with a plethysmometerwere measured. Subcutaneous (s.c.) treatment with(−)-MRV3 (1, 2, 3, 4, 5 mg/kg) dose-dependentlyreduced allodynia and hyperalgesia induced byintraplantar carageenan. Furthermore, treatment with(−)-MRV3 (3 mg/kg s.c.) also inhibited paw edemawith a significant inhibition of 61.53 % 3 h aftercarrageenan treatment [corrected]. These results provide a strongbasis for the use of σ1 receptor antagonists in thetreatment of inflammatory pain.

Trail interacts redundantly with nitric oxide in rat astrocytes: potential contribution to neurodegenerative processes.

The proapoptotic cytokine TRAIL has been shown to enhance amyloid-beta-dependent neurotoxicity. Here are reported interactions between TRAIL and nitric oxide (NO) in cultured rat astrocytes in vitro. Rat astrocytes expressed all TRAIL receptor mRNAs and proteins. However, TRAIL failed in inducing apoptosis of astrocytes, whereas these cells released substantial amounts of nitrites. A TRAIL-neutralizing antibody was able to prevent LPS-induced iNOS expression in astrocytes. Interestingly, TRAIL induced its own expression in astrocytes. These data suggest that redundancy between TRAIL and NO in astrocytes could be fueling neuronal damage/death processes, potentially uncovering novel molecular targets for the treatment of neurodegenerative disorders.

In vivo evaluation of (+)-MR200 as a new selective sigma ligand modulating MOP, DOP and KOP supraspinal analgesia.

The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a sigma ligand with increased affinity and selectivity compared to the structurally related ligand haloperidol. From the results of a previous study on the modulation of a systemically injected KOP opioid agonist analgesia by (+)-MR200, we analysed the influence of this sigma ligand on the antinociceptive effect of centrally injected MOP, DOP, and KOP selective agonists using the tail-flick test in rats. The results obtained confirmed that systemic administration of (+)-MR200 (1mg/Kg s.c.) did not modify basal tail-flick latency. Pre-treatment with 1mg/Kg s.c. of (+)-MR200 provided a significant increase in the antinociceptive effect of DAMGO (100ng/rat i.c.v.) and DPDPE (20 microg/rat i.c.v.). Conversely to previous reports, pre-treatment with (+)-MR200 reversed, in these experimental conditions, U-50488H (100 microg/rat i.c.v.) analgesia. The mechanism involved in these effects was not clear, but provided additional data on a diverging modulator role of selective sigma-1 antagonists on KOP analgesia.

Effect of supraspinal Nocistatin on Nociceptin/Orphanin FQ antagonism of selective opioid analgesia.

Nocistatin and Nociceptin/Orphanin FQ are two neuropeptides derived from the same precursor protein, pre-pro-Nociceptin. Nocistatin does not bind to Nociceptin/Orphanin FQ peptide (NOP) receptor but it antagonizes the allodynic and hyperalgesic effect of intrathecal (i.t.) Nociceptin. In this study, we examined the effect of Nocistatin on nociception and opioid analgesia by itself and the nociceptive effect of Nociceptin and antagonistic effect of nociceptin on opioid receptors in tail flick test when given the i.c.v. route. More precisely, supraspinal Nocistatin by itself had no significative effect on nociception and opioid analgesia in the tail flick test but, at the dose of 0.5ng/rat, it reversed the nociceptive effect of Nociceptin and also the antagonistic effect of Nociceptin against analgesia caused by the selective opioid agonists: DAMGO, DPDPE, Deltorphin II and U50 488H. These data suggest that Nocistatin antagonizes the effect of Nociceptin on opioid analgesia and could play an important role in the regulation of nociceptive transmission.

Growth hormone protects human lymphocytes from irradiation-induced cell death.

1. Undesired effects of cancer radiotherapy mainly affect the hematopoietic system. Growth hormone (GH) participates in both hematopoiesis and modulation of the immune response. We report both r-hGH cell death prevention and restoration of secretory capacities of irradiated human peripheral blood lymphocytes (PBL) in vitro. 2. r-hGH induced cell survival and increased proliferation of irradiated cells. Western blot analysis indicated that these effects of GH were paralleled by increased expression of the antiapoptotic protein Bcl-2. 3. r-hGH restored mitogen-stimulated release of IL-2 by PBL. Preincubation of irradiated lymphocytes with the growth hormone receptor (GHR) antagonists B2036 and G120 K abrogated r-hGH-dependent IL-2 release. 4. These results demonstrate that r-hGH protects irradiated PBL from death in a specific, receptor-mediated manner. Such effect of r-hGH on PBL involves activation of the antiapoptotic gene bcl-2 and prevention of cell death, associated with preserved functional cell capacity. Finally, potential use of GH as an immunopotentiating agent could be envisioned during radiation therapy of cancer.