Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

Este proyecto se redacta como definición de la reforma del local mencionado con anterioridad, para su explotación comercial como tienda de conveniencia. El acceso principal se realiza desde la calle Felip II. Se plantea una separación funcional del local. En la planta baja se sitúan la zona de venta con las cajas de cobro, dos aseos aseo para el público y el oficio de panadería con su mostrador correspondiente. La planta baja comunica a través de una escalera y una plataforma montacargas con una entreplanta, denominada “altillo” en los planos. Aquí se ubican los espacios de acceso restringido: los vestuarios y aseos del personal, almacén, cuarto de control del almacén, cuarto de mercancía valiosa, cuarto de informática, cuarto de limpieza y cuarto de basuras. El almacén comunica directamente con la planta baja mediante una plataforma montacargas, situada cerca del acceso al local

A bivalent compound targeting CCR5 and the mu opioid receptor treats inflammatory arthritis pain in mice without inducing pharmacologic tolerance

Abstract Background Pain accompanies rheumatoid arthritis and other chronic inflammatory conditions and is difficult to manage. Although opioids provide potent analgesia, chronic opioid use can cause tolerance and addiction. Recent studies have demonstrated functional interactions between chemokine and opioid receptor signaling pathways. Reported heterodimerization of chemokine and opioid receptors led our group to develop bivalent compounds that bind both types of receptors, with the goal of targeting opioids to sites of inflammation. MCC22 is a novel bivalent compound containing a CCR5 antagonist and mu opioid receptor (MOR) agonist pharmacophores linked through a 22-atom spacer. We evaluated the efficacy of MCC22 in the K/B.g7 T-cell receptor transgenic mouse model of spontaneous inflammatory arthritis. Methods MCC22 or morphine was administered intraperitoneally at varying doses to arthritic K/B.g7 mice or nonarthritic control mice. Mechanical pain hypersensitivity was measured each day before and after drug administration, using the electronic von Frey test. The potency of MCC22 relative to that of morphine was calculated. Functional readouts of pain included grip strength and nesting behavior. A separate dosing regimen was used to determine whether the drugs induced pharmacologic tolerance. Results MCC22 provided ~ 3000-fold more potent analgesia than morphine in this model. Daily treatment with MCC22 also led to a cumulative analgesic effect, reducing the daily baseline pain level. MCC22 produced no observable analgesic effect in nonarthritic control mice. Importantly, repeated administration of MCC22 did not induce pharmacologic tolerance, whereas a similar regimen of morphine did. Both grip strength and nesting behaviors improved among arthritic mice treated with MCC22. Ankle thickness and arthritis scores were not affected by MCC22. The analgesic effect of MCC22 was abolished in K/B.g7 mice genetically lacking CCR5, demonstrating the receptor specificity of the antagonist pharmacophore. Conclusions MCC22 is a novel bivalent ligand that targets CCR5 and MOR. Our findings demonstrate that MCC22 provides highly potent analgesia and improved functional outcomes in a model of inflammatory arthritis, without inducing typical opioid tolerance. These findings suggest that MCC22 or similar compounds could be used to treat the pain associated with inflammatory arthritis and related conditions, while minimizing the risks typically associated with chronic opioid use

Additional file 1: of A bivalent compound targeting CCR5 and the mu opioid receptor treats inflammatory arthritis pain in mice without inducing pharmacologic tolerance

Figure S1. Structure of MCC22. MCC22 is a bivalent pharmacophore comprising a mu opioid receptor (MOR) agonist and a CCR5 antagonist joined by a 22-atom spacer. Figure S2. Representative histologic sections. The images show histologic sections of ankles from nonarthritic control animals and arthritic K/B.g7 mice treated with vehicle (DMSO) or daily MCC22 for 9 days (8 μmol/kg/dose). Photomicrographs were obtained with a 4× objective. Scale bars = 500 μm. (PDF 3747 kb