The signaling lipid sphingosine 1-phosphate regulates mechanical pain

Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli. These effects are mediated by fast-conducting A mechanonociceptors, which displayed a significant decrease in mechanosensitivity in S1PR3 mutant mice. We show that S1PR3 signaling tunes mechanonociceptor excitability via modulation of KCNQ2/3 channels. Our findings define a new role for S1PR3 in regulating neuronal excitability and establish the importance of S1P/S1PR3 signaling in the setting of mechanical pain thresholds

Synergistic Actions of Mu-Opioid and CB2 Receptor Agonists in Rodent Models of Acute and Chronic Pain

The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Furthermore, activation of cannabinoid 2 (CB2) receptors on immune cells through the inhibition of monoacylglycerol lipase (MAGL), results in increased 2-arachidonylglycerol (2AG) production and analgesia in animal models. Yet, few studies have identified whether mu opioid and CB2 receptor agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability, or if it could ameliorate the excruciating pain that is poorly managed with by opiates in bone cancer patients. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, or the inhibitor of MAGL, MJN110, in rodent models of acute and chronic inflammatory, post-operative, neuropathic, and cancer-induced bone pain (CIBP) using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Next, we examined whether JWH015 or the inhibition of MAGL decreased the release of pro-inflammatory mediators by activating nuclear factor kappa enhancer of activated B cells (NFkB), as dysregulation of NFkB is observed in various cancers. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.Release after 21-Nov-201

¿Risco colonialista en Panamá?

El objetivo inmediato del estudio es transmitir conocimientos especializados con base en líneas teóricas actuales acerca del recurso metaliterario, el cual es la zona autorreflexiva de la escritura. Como el recurso tiene la función de comentario en el interior de la producción literaria, se analizarán los efectos de retorno a la realidad cultural histórica de la sedimentada colonialidad que no se ha superado en Panamá, pero este retorno es literario, puesto que la literatura histórica expresa; sin embargo, no se escribe como metaliteratura. Los resultados han sido de gran beneficio porque las producciones literarias demuestran la importante presencia del tratamiento metaliterario y la referencia internacional adaptada por la competencia creativa de los escritores panameños

Japanese armor (image)

Summer Issuehttp://deepblue.lib.umich.edu/bitstream/2027.42/61006/1/3002.pd

Morphine-induced osteolysis and hypersensitivity is mediated through toll-like receptor-4 in a murine model of metastatic breast cancer

The propensity for breast cancer to metastasize to bone is coupled to the most common complaint among breast cancer patients: bone pain. Classically, this type of pain is treated using escalating doses of opioids, which lack long-term efficacy due to analgesic tolerance, opioid-induced hypersensitivity, and have recently been linked to enhanced bone loss. To date, the molecular mechanisms underlying these adverse effects have not been fully explored. Using an immunocompetent murine model of metastatic breast cancer, we demonstrated that sustained morphine infusion induced a significant increase in osteolysis and hypersensitivity within the ipsilateral femur through the activation of toll-like receptor-4 (TLR4). Pharmacological blockade with TAK242 (resatorvid) as well as the use of a TLR4 genetic knockout ameliorated the chronic morphine-induced osteolysis and hypersensitivity. Genetic MOR knockout did not mitigate chronic morphine hypersensitivity or bone loss. In vitro studies using RAW264.7 murine macrophages precursor cells demonstrated morphine-enhanced osteoclastogenesis that was inhibited by the TLR4 antagonist. Together, these data indicate that morphine induces osteolysis and hypersensitivity that are mediated, in part, through a TLR4 receptor mechanism.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]