RESUMEN
Kappa opioid receptor (KOR) agonists possess adverse dysphoric and psychotomimetic effects, thus limiting their applications as non-addictive anti-pruritic and analgesic agents. Here, we showed that protein kinase C (PKC) inhibition preserved the beneficial antinociceptive and antipruritic effects of KOR agonists, but attenuated the adverse condition placed aversion (CPA), sedation, and motor incoordination in mice. Using a large-scale mass spectrometry-based phosphoproteomics of KOR-mediated signaling in the mouse brain, we observed PKC-dependent modulation of G protein-coupled receptor kinases and Wnt pathways at 5 min; stress signaling, cytoskeleton, mTOR signaling and receptor phosphorylation, including cannabinoid receptor CB1 at 30 min. We further demonstrated that inhibition of CB1 attenuated KOR-mediated CPA. Our results demonstrated the feasibility of in vivo biochemical dissection of signaling pathways that lead to side effects.
Asunto(s)
Proteína Quinasa C/genética , Receptores Opioides kappa/genética , Transducción de Señal/efectos de los fármacos , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Animales , Reacción de Prevención , Quinasas de Receptores Acoplados a Proteína-G , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Fosfoproteínas , Fosforilación , Proteína Quinasa C/efectos de los fármacos , Proteína Quinasa C/efectos de la radiación , Inhibidores de Proteínas Quinasas , Proteómica , Receptor Cannabinoide CB1/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides kappa/efectos de la radiación , Serina-Treonina Quinasas TOR/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
A brief exposure to a pulsed magnetic field (Cnp: patent pending) had significant antinociceptive or "analgesic" effects in the land snail, Cepaea nemoralis, as evidenced by an increase in the latency of response to a warmed (40 degrees C) surface. This analgesia was in part opioid mediated being significantly reduced, but not eliminated: by the prototypic opiate antagonist, naloxone; the mu (mu) opioid receptor directed antagonists, naloxazine or beta-funaltrexamine, and the delta (delta) opioid receptor directed antagonists, naltrindole-5'-isothiocyanate or ICI 174,864. However the Cnp induced analgesia was unaffected by the kappa (kappa) opioid receptor directed antagonist, nor-binaltorphimine. The delta 1 and delta 2 opioid receptor directed agonists, (DPDPE, [D-Pen2,D-Pen5]enkephalin), (deltorphin, [D-Ala2,Glu4]), respectively, also had significant differential analgesic effects, supporting a functional delta opioid receptor mediated enkephalinergic mechanism in Cepaea. These results suggest that this specific pulsed magnetic field (Cnp) elicits significant analgesic effects through mechanisms that, in part, involve delta and, to a lesser extent mu opioid receptors.
