The existence of μ, δ and κ opioid receptors in the central nervous system is well documented. The present review focuses on the relationships between opioid receptor types and physical and psychic dependences. Mu and δ, but not κ opioid receptor agonists produce physical dependence. From behavioral, biochemical and molecular biological studies, it is suggested so far that development of physical dependence on morphine results predominantly from an activation of μ1 and μ2 opioid receptors which causes functional changes in Gi/o, adenylate cyclase, protein kinases A and C, β-adrenoceptor and NMDA receptor in the locus coeruleus. Recently, there have been significant advances in studies on psychic dependence. Mu and δ opioid receptor agonists produce psychic dependence, but κ opioid receptor agonists rather produce an aversive effect. Activation of the mesolimbic dopamine system may lead to psychic dependence on opioids. Mu and δ1 opioid receptor agonists activate the mesolimbic dopamine system to induce a rewarding effect, whereas the rewarding effect of δ2 opioid receptor agonists may be produced through a nondopaminergic system. There are complicated interactions among opioid receptor types. The activation of κ opioid receptor suppresses physical and psychic dependences on μ and δ opioid receptor agonists, but the activation of δ opioid receptor potentiates the dependence on μ opioid receptor agonists. The clinical use of morphine in patients with cancer pain won't develop dependence probably due to the balance of the opioid system coming from these interactions.
We have established a novel thrombosis model of the middle cerebral artery (MCA). The thrombotic occlusion of the MCA was induced by the photochemical reaction between Rose Bengal and green light, which causes endothelial injury followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of the photochemical reaction. With this model, we have investigated the effects of anti-thrombotic agents, thrombolytic agents and neuroprotective agents. In our model, ADP, thromboxane A2 (TXA2) and thrombin play a key role in thrombus formation of the MCA. Tissue-type plasminogen activator (tPA) could cause an opening of the thrombotic MCA occlusion and reduced the size of the cerebral infarction. Furthermore, a TXA2 antagonist enhanced the thrombolytic efficacy of tPA. MS-153 ((R)-(-)-5methyl-1-nicotinoyl-2-pyrazoline), a glutamate release inhibitor and YM90K [6-(1 H-imidazol-lyl)-7-nitro-2, 3(1H, 4H)-qunoxalinedione monohydrochloride], an α -amino-3hydroxy-5methyl-4isoxazole (AMPA) antagonist reduced the cerebral infarction 24 hr after the MCA occlusion. This model is very useful for investigating the mechanisms of anti-thrombotic and neuroprotective agents and evaluating the effects of these agents.
The synthetic oligodeoxynucleotide (ODN) complementary to the normal (sense) mRNA, socalled antisense ODN, has been used to regulate the gene expression in the brain. It has been reported to interfere with transcription, pre-mRNA splicing and translation through at least two mechanisms; i.e., its competition with transcription and protein synthesis machinery or induction of mRNA cleavage. The unmodified antisense ODN was shown to be the RNase activator when it hybridizes with at least four contiguous bases of mRNA. In contrast, the phosphorothioate ODN (S-ODN) is reported to be a less effective activator of RNase H and more resistant to the nuclease attack than unmodified ODN. Because of these properties, S-ODNs are preferentially employed in antisense ODN experiments. When the DNA sequence of the target gene is determined, we can design an antisense ODN that selectively hybridizes with the bases of a nucleic acid (DNA or RNA) related to the target gene. The initial sites of specific binding of most drugs are known to be proteins such as receptors and enzymes. Therefore, the specific modulation of target protein synthesis by the antisense ODN method is quite interesting to the pharmacologist. We have studied the change in the morphine-induced behaviors after the microinjection of antisense S-ODN directed against the m-opioid receptor (MOR) into the periaqueductal gray (PAG) or lateral ventricle of rat brain. We could detect the decrease of the MOR mRNA level in PAG by the RT-PCR method and that in whole brain by the Northern blot technique. Although the antisense ODN method seems to be quite useful for the modulation of a given gene expression, many problems still remain to be elucidated. These include the mechanism of the regulation of a target gene, pharmacokinetics of antisense ODN and toxicity of antisense ODN.