The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, prochlorperazine and caffeine, compared to sumatriptan, in an in vivo model.

A hypofunctionality of Gi proteins has been found in migraine patients. The fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) is a drug of well-established use in the acute treatment of migraine and tension-type headache. The aim of this study was to investigate if Indoprocaf was able to exert its central antinociceptive action when Gi proteins activity is abolished by pertussis toxin (PTX), compared to its single active ingredients and to sumatriptan. The mice model of abdominal constriction test induced by an i.p. injection of a 0.6% solution of acetic acid was used. The study showed that Indoprocaf (a fixed combination of indomethacin 1 mg/kg, prochlorperazine 1 mg/kg and caffeine 3 mg/kg, s.c.) and sumatriptan (20 mg/kg, s.c.) exert their central antinociceptive action independently from the Gi proteins. In addition, the antinociceptive efficacy of Indoprocaf in this study was statistically superior to that of sumatriptan. This study also showed that the single active ingredients of Indoprocaf, indomethacin (1 mg/kg, s.c.), prochlorperazine (1 mg/kg, s.c.) and caffeine (3 mg/kg, s.c.), were able to exert their central antinociceptive action independently from the Gi proteins. However, Indoprocaf at analgesic doses was able to abolish almost completely the abdominal constrictions, with a statistically higher efficacy compared to the single active ingredients, showing an important synergic effect of Indoprocaf. This synergic effect was evident not only when Gi proteins activity was abolished by PTX, but also under control condition, when Gi proteins were active. This study suggests that the central antinociceptive action induced by antimigraine drugs is independent from Gi proteins

St. John's Wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase C γ and ɛ activity

International audienceCurrent pharmacological treatments for neuropathic pain have limited efficacy and severe side-effect limitations. St. John's Wort (SJW) is a medicinal plant, mainly used as antidepressant, with a favourable side-effect profile. We here demonstrate the ability of SJW to relieve neuropathic pain in rat models. The antihyperalgesic profile and mechanism of action of SJW and its main components was studied in two rat models of neuropathic pain: the chronic constriction injury and the repeated administration of oxaliplatin. SJW, acutely administered at low doses (30-60mgkg p.o.), reversed mechanical hyperalgesia with a prolonged effect, being effective up to 180min after injection. Further examinations of the SJW main components revealed that hyperforin and hypericin were responsible for the antihyperalgesic properties whereas flavonoids were ineffective. The effect of SJW on the PKC expression and activation was investigated in the periaqueductal grey (PAG) area by immunoblotting experiments. Mechanistic studies showed a robust over-expression and hyperphosphorylation of the PKC-γ (227.0±15.0% of control) and -ɛ (213.9±17.0) isoforms in the rat PAG area. A single oral administration of SJW produced a significant decrease of the PKC-γ (131.8±10.0) and -ɛ (105.2±12.0) phosphorylation in the PAG area due to the presence of hypericin. Furthermore, SJW showed a dual mechanism of action since hyperforin antinociception involves an opioid-dependent pathway. Rats undergoing treatment with SJW and purified components did not show any behavioural side effects or signs of altered locomotor activity. Our results indicate SJW as a prolonged antihyperalgesic treatment through inhibition of PKC isoforms and their phosphorylation

A case of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially fatal complication of pulmonary embolism (PE). Organized thrombus in the pulmonary artery causes a chronic obstruction, leading to a vascular system remodeling, an increase of pulmonary vascular resistance and a chronic pulmonary hypertension. Epidemiology is mostly unknown due to the difficult diagnostic process that often leads to a late diagnosis: findings of persistent pulmonary hypertension (PH), despite correct treatment of PE, lead to the diagnostic suspect. The first choice treatment is pulmonary endarterectomy (PEA) associated with lifelong anticoagulant therapy with vitamin K antagonist. We present the case of a 53-year-old male affected by dyspnea for months, admitted to a sub-intensive care unit for intermediate low-risk PE; echocardiography showed signs of PH persisting after anticoagulant therapy; after 2 months of specific treatment the diagnosis of CTEPH was confirmed and the patient was successfully treated with PEA

Antihyperalgesic activity of verbascoside in two models of neuropathic pain.

Abstract Objectives This study reports on the rapid isolation of verbascoside from Lippia citriodora H.B.K. (Verbenaceae), an inexpensive and widespread source, and the evaluation of its antihyperalgesic activity. Methods Isolation of verbascoside was achieved by size exclusion chromatography with Sephadex LH-20 eluting with 50% EtOH, which is proposed as a fast and efficient method of separation. Key findings The antihyperalgesic activity of verbascoside was tested by in-vivo assay using the paw-pressure test in two animal models of neuropathic pain: a peripheral mononeuropathy produced either by a chronic constriction injury of the sciatic nerve (CCI) or by an intra-articular injection of sodium monoiodoacetate (MIA). Conclusions Verbascoside administered intraperitoneally at a dose of 100 mg/kg reverted the mechanical hyperalgesia in both CCI and MIA treated rats, as evaluated in the paw-pressure test. Verbascoside was also effective against mechanical hyperalgesia after oral administration at doses of 300 and 600 mg/kg. </jats:sec