|Budget Amount *help
¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 1999 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1998 : ¥1,900,000 (Direct Cost : ¥1,900,000)
The present study was designed to investigate several kinds of pharmacological action of (-) and (+)TAN-67, the enantiomorphis of TAN-67, which is a highly selective non-peptidec δ opioied receptor agonist. Neither subcutaneous (s.c.) nor intracerebroventricular (i.c.v.) injection of (-)TAN-67 enhanced locomotor activity. Unlike morphine, chronic treatment with (-)TAN-67 failed to develop either physical or psychological dependence.
The microdialysis study was performed to detect variations in extracellular dopamine and its metabolites in the nucleus accumbens of freely moving rats following acute s.c. injection of (-)TAN-67. (-)TAN-67 had no effect on the release of dopamine and its metabolites in the nucleus accumbens of rats, which is a key area to elicit a motivational effect by abused drugs. Like (-)TAN-67, (+)TAN-67 did not produce hyperlocomotion, dopamine release, physical and psychological dependence.
With respect to the nociception, either i.c.v. or intrathecal (i.t.) injection
of (-)TAN-67 prolonged the tail-flick and warm-plate latencies through δ-opioid receptors, whereas i.t.injection of (+)TAN-67 induced pain-like nociceptive behaviors. It should be noteworthy that the (+)TAN-67-induced nociception lasted for a couple of days following the injection, and this effect was attenuated by either δ-opioid receptor agonists or antagonists. It is of interest to note that the (+)TAN-67-induced nociception was markedly suppressed by κ-opioid receptor agonists, but not by μ-opioid receptor agonists. Furthermore, the (+)TAN-67-induced nociception was modulated by spinal GABAergic and glutamatergic systems. In order to ascertain the intracellular mechanisms of the (+)TAN-67-induced nociception, a specific protein kinase C (PKC) inhibitor was injected i.t. Prior to (+)TAN-67 injection. A PKC inhibitor produced a siginificant righward-sift of the dose-response curve for the nociception induced by i.t.injection of ()TAN-67. More interestingly, a single i.t. injection of (+)TAN-67 caused a specific up-regulation of levels of PKCィイD2γィエD2 isoform in membranes of the spinal cord. These findings suggest the possibility that, like neuropathic pain, a single i.t. injection of (+)TAN-67 may induce the sensitization of NMDA receptors via the concomitant facilitation of PKCィイD2γィエD2. Thus, it is likely that the nociception caused by (+)TAN-67 given i.t. could be a useful pharmacological model for elucidation of the pain mechanisms in the spinal cord. Less