PubMed · 7437232
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R F Cookson. 1980. Analgesic plasma concentrations.. https://doi.org/10.1093/bja%2F52.9.959-a
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Several isoforms of neuronal nitric oxide synthase (nNOS) have been identified. Antisense approaches have been developed which can selectively down-regulate nNOS-1, which corresponds to the full-length nNOS originally cloned from the brain, and nNOS-2, a truncated form lacking two exons which is generated by alternative splicing, as demonstrated by decreases in mRNA levels. Antisense treatment also lowers nNOS enzymatic activity. Down-regulation of nNOS-1 prevents the development of morphine tolerance. Whereas morphine analgesia is lost in control and mismatch-treated mice given daily morphine injections for 5 days, mice treated with antisense probes targeting nNOS-1 show no decrease in their morphine sensitivity over the same time period. Conversely, an antisense probe selectively targeting nNOS-2 blocks morphine analgesia, shifting the morphine dose-response curve over 2-fold to the right. Both systems are active at the spinal and the supraspinal levels. An antisense targeting inducible NOS is inactive. Studies with NG-nitro-L-arginine, which does not distinguish among NOS isoforms, indicate that the facilitating nNOS-2 system predominates at the spinal level while the inhibitory nNOS-1 system is the major supraspinal nNOS system. Thus, antisense mapping distinguishes at the functional level two isoforms of nNOS with opposing actions on morphine actions. The ability to selectively down-regulate splice variants opens many areas in the study of nNOS and other proteins.
A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an orthogonal-oriented "address" for delta opioid receptors. All of the ligands exhibited a preference for delta receptors in vitro. The 7-benzospiroindanyl derivative 8 (BSINTX) was the most selective delta opioid receptor antagonist in vitro. In mice BSINTX antagonized the delta 1-selective agonist, [D-Pen2,D-Pen5]enkephalin without significantly affecting the antinociceptive potency of delta 2, mu, and kappa agonists. The results of this study are consistent with an orthogonally-oriented address favoring delta 1 activity.
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