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The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.

Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. We tested this hypothesis using a rat model of neonatal maternal separation (NMS) known to induce long-term consequences on several brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. We found that adult rats with a history of NMS were hypersensitive to noxious mechanical/thermal hot stimuli and to inflammatory pain. We failed to observe OT receptor-mediated stress-induced analgesia and OT antihyperalgesia after carrageenan inflammation. These alterations were partially rescued if NMS pups were treated by intraperitoneal daily injection during NMS with OT or its downstream second messenger allopregnanolone. The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor-mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.

Background Lithium is widely used to treat bipolar disorders and displays mood stabilizing properties. In addition, lithium relieves painful cluster headaches and has a strong analgesic effect in neuropathic pain rat models. Objectives To investigate the analgesic effect of lithium on the cuff model of neuropathic pain. Methods We used behavioral and pharmacological approaches to study the analgesic effect of a single injection of lithium in wild-type and mu opioid receptor (MOR) null cuffed neuropathic mice. Mass spectrometry and enzyme-linked immunosorbent assay allowed to measure the levels of endogenous MOR agonist beta-endorphin as well as monoamines in brain and plasma samples 4 h after lithium administration. Results A single injection of lithium chloride (100 mg/kg, ip) alleviated mechanical allodynia for 24 h, and this effect was absent in MOR null neuropathic mice. Biochemical analyses highlight a significant increase in beta-endorphin levels by 30% in the brain of lithium-treated mice compared to controls. No variation of beta-endorphin was detected in the blood. Conclusions Together, our results provide evidence that lithium induces a long-lasting analgesia in neuropathic mice presumably through elevated brain levels of beta-endorphin and the activation of MORs.

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Expression of beta(2)-adrenoceptors (beta(2)-ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of beta(2)-ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of beta(2)-ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the beta(2)-AR antagonist ICI 118,551 or a transgenic approach with mice deficient for beta(2)-ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on beta(2)-ARs. We also showed that chronic treatment with the beta(1)-AR agonist xamoterol or with the beta(3)-AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of beta(2)-ARs, but not beta(1)- or beta(3)-ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of beta(2)-AR agonists might implicate the endogenous opioid system; indeed chronic clenbuterol effect can be acutely blocked by the delta-opioid receptor antagonist naltrindole. Present results show that beta(2)-ARs are not only essential for the antiallodynic action of antidepressant drugs on sustained neuropathic pain, but also that the stimulation of these receptors is sufficient to relieve neuropathic allodynia in a murine model. Our data suggest that beta(2)-AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain.

Neuropathic pain is a disease caused by a lesion or dysfunction of the nervous system. Antidepressants or anticonvulsants are presently the best available treatments. The mechanism by which antidepressants relieve neuropathic pain remains poorly understood. Using pharmacological and transgenic approaches in mice, we evaluated adrenergic receptor (AR) implication in the action of the tricyclic antidepressant desipramine, the noradrenaline and serotonin reuptake inhibitor venlafaxine, and the noradrenaline reuptake inhibitor reboxetine. Neuropathy was induced by cuff insertion around the sciatic nerve. We showed that chronic antidepressant treatment suppressed cuff-induced allodynia in wild-type mice but not in beta(2)-AR deficient mice, and/or that this antiallodynic action was blocked by intraperitoneal or intrathecal injection of the beta(2)-AR antagonist ICI 118,551 but not by the alpha(2)-AR antagonist yohimbine. We also showed that the anticonvulsant gabapentin was still effective in beta(2)-AR deficient mice. Our results demonstrate that beta(2)-ARs are essential for the antiallodynic action of antidepressant drugs.