21 research outputs found
Selectivity of δ- and κ-Opioid Ligands Depends on the Route of Central Administration in Mice
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
Targeting Putative Mu Opioid/Chemokine Receptor Type 5 Heteromers Potently Attenuates Nociception in a Murine Model of Sickle Cell Disease
Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice
Central
administration of melanocortin ligands has been used as
a critical technique to study energy homeostasis. While intracerebroventricular
(ICV) injection is the most commonly used method during these investigations,
intrathecal (IT) injection can be equally efficacious for the central
delivery of ligands. Importantly, intrathecal administration can optimize
exploration of melanocortin receptors in the spinal cord. Herein,
we investigate comparative IT and ICV administration of two melanocortin
ligands, the synthetic MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH<sub>2</sub>) MC4R agonist and agouti-related peptide [AGRP(87-132)] MC4R
inverse agonist/antagonist, on the same batch of age-matched mice
in TSE metabolic cages undergoing a nocturnal satiated paradigm. To
our knowledge, this is the first study to test how central administration
of these ligands directly to the spinal cord affects energy homeostasis.
Results showed, as expected, that MTII IT administration caused a
decrease in food and water intake and an overall negative energy balance
without affecting activity. As anticipated, IT administration of AGRP
caused weight gain, increase of food/water intake, and increase respiratory
exchange ratio (RER). Unexpectantly, the prolonged activity of AGRP
was notably shorter (2 days) compared to mice given ICV injections
of the same concentrations in previous studies (7 days or more).− It appears that IT administration results in a more sensitive response
that may be a good approach for testing synthetic compound potency
values ranging in nanomolar to high micromolar in vitro EC<sub>50</sub> values. Indeed, our investigation reveals that the spine influences
a different melanocortin response compared to the brain for the AGRP
ligand. This study indicates that IT administration can be a useful
technique for future metabolic studies using melanocortin ligands
and highlights the importance of exploring the role of melanocortin
receptors in the spinal cord
Clinically Employed Opioid Analgesics Produce Antinociception via μ‑δ Opioid Receptor Heteromers in Rhesus Monkeys
Morphine and related drugs are widely employed as analgesics
despite
the side effects associated with their use. Although morphine is thought
to mediate analgesia through mu opioid receptors, delta opioid receptors
have been implicated in mediating some side effects such as tolerance
and dependence. Here we present evidence in rhesus monkeys that morphine,
fentanyl, and possibly methadone selectively activate mu-delta heteromers
to produce antinociception that is potently antagonized by the delta
opioid receptor antagonist, naltrindole (NTI). Studies with HEK293
cells expressing mu-delta heteromeric opioid receptors exhibit a similar
antagonism profile of receptor activation in the presence of NTI.
In mice, morphine was potently inhibited by naltrindole when administered
intrathecally, but not intracerebroventricularly, suggesting the possible
involvement of mu-delta heteromers in the spinal cord of rodents.
Taken together, these results strongly suggest that, in primates,
mu-delta heteromers are allosterically coupled and mediate the antinociceptive
effects of three clinically employed opioid analgesics that have been
traditionally viewed as mu-selective. Given the known involvement
of delta receptors in morphine tolerance and dependence, our results
implicate mu-delta heteromers in mediating both antinociception and
these side effects in primates. These results open the door for further
investigation in humans