ABSTRACT
High affinity and saturable nociceptin (orphanin FQ) receptors were detected and characterized in adult rat and human fetal hypothalamic membranes, utilizing [125I]Tyr12-nociceptin as ligand. Nociceptin bound with picomolar affinity, dynorphin A with nanomolar affinity, naloxone and dynorphan A(1-8) with micromolar while des-Tyr1-dynorphin (dynorphin A(2-17)), several other opioids, morphine and benzomorphans failed to compete for binding at 1-10 microM. Gpp(NH)p together with sodium ion markedly decreased binding, consistent with involvement of a G protein-linked receptor.
Subject(s)
Hypothalamus/chemistry , Receptors, Opioid/analysis , Animals , Binding, Competitive/physiology , Female , Fetus/chemistry , GTP-Binding Proteins/metabolism , Humans , Hypothalamus/embryology , Iodine Radioisotopes , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Opioid/metabolism , Nociceptin ReceptorSubject(s)
Autoimmune Diseases/drug therapy , Demyelinating Diseases/drug therapy , Dronabinol/therapeutic use , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Immunosuppressive Agents/therapeutic use , Neuritis, Autoimmune, Experimental/drug therapy , Animals , Autoimmune Diseases/immunology , Demyelinating Diseases/immunology , Disease Models, Animal , Dronabinol/pharmacology , Drug Evaluation, Preclinical , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Lymphocyte Activation/drug effects , Male , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Neuritis, Autoimmune, Experimental/immunology , Neuritis, Autoimmune, Experimental/pathology , Polyradiculoneuropathy/drug therapy , Polyradiculoneuropathy/immunology , Rats , Rats, Inbred LewABSTRACT
Since multiple sclerosis (MS) is believed to be an immune-mediated disease, it follows that its therapies should be directed towards modulating the immune system. Current MS treatments, which include the use of exogenous steroids that are immunosuppressive, do not meet therapeutic objectives. delta 9-Tetrahydrocannabinol (THC), an active component of marijuana, has been shown to be immunosuppressive. To test THC's ability to suppress an immune-mediated disease, experimental autoimmune encephalomyelitis (EAE), the laboratory model of MS, was used. Lewis rats and strain 13 guinea pigs were administered THC either before inoculation for EAE or treated with THC after injection. Control animals received placebo. The effect of dose, in addition to the timing of treatment, was also investigated. All animals treated with placebo developed severe clinical EAE 10-12 days post-injection (d.p.i.) and more than 98% died by 15 d.p.i. THC-treated animals had either no clinical signs or mild signs with delayed onset (13-15 d.p.i.) with survival greater than 95%. Examination of central nervous system tissue revealed a marked reduction of inflammation in the THC-treated animals. Therefore, as THC has been shown to inhibit both clinical and histologic EAE, it may prove to be a new and relatively innocuous agent for the treatment of immune-mediated diseases.