The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · May 1996
Pharmacokinetic properties of several novel oligonucleotide analogs in mice.
Biophysical and pharmacokinetic properties of five analogs of ISIS 3082, a 20-mer phosphorothioate oligodeoxynucleotide that inhibits the expression of mouse intercellular adhesion molecule 1, were evaluated. Compared to the parent compound, ISIS 3082, the 2'-propoxy modified phosphodiester, ISIS 9044 and the 2'-propoxy phosphorothioate, ISIS 9045, had greater affinity for complementary RNA and were more lipophilic. A chimeric oligonucleotide comprised of 2'-propoxy diester wings and a phosphorothioate deoxy center (ISIS 9046) had equal affinity. ⋯ The rate of metabolism of ISIS 9044 (2'-propoxy phosphodiester oligonucleotide) was much more rapid in liver and plasma, but surprisingly much slower in the kidney. ISIS 9045 (full 2-propoxy phosphorothioate) was much more stable than ISIS in all tissues, the enhanced stability of ISIS 9045 resulted in increased exposure of liver and kidney to the drug, whereas the exposure of the liver to the two more lipophilic analogs, ISIS 9047 and ISIS 8005, was greater because a higher fraction of the dose was distributed to the liver. The exposure of the kidney to ISIS 9044 was also greater than that to ISIS 3082 due to the surprising stability of the drug in the kidney.
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J. Pharmacol. Exp. Ther. · May 1996
Electrical stimulation at traditional acupuncture sites in periphery produces brain opioid-receptor-mediated antinociception in rats.
Previous studies in rats measuring latency to tail flick with radiant heat have shown that the antinociceptive effect induced by electrical stimulation of different frequencies at traditional acupuncture sites is mediated via different opioid receptors in the spinal cord. The present study was designed to observe (1) whether electrical stimulation at such sites could produce antinociceptive effects in the cold water tail-flick (CWT) test; (2) whether the antinociceptive effects could be blocked by s.c. injection of the opioid receptor antagonist naloxone and (3) whether i.c.v. injection of selective antagonists for mu (cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, CTAP), delta (naltrindole) or kappa (nor-binaltorphimine) opioid receptors would block the antinociceptive effect produced by electrical stimulation. Sprague-Dawley rats were stimulated at frequencies of 2, 30 or 100 Hz with acupuncture needles inserted into acupoints Zusanli and Sanyinjiao in the hind leg for 30 min. ⋯ The results showed that (1) a significant, frequency-related increase in threshold in the CWT was observed in all electrical stimulation groups as compared with the placebo group and the antinociceptive effect lasted about 30 min poststimulation; (2) naloxone (s.c.) antagonized the antinociceptive effect induced by 2 Hz, 30 Hz or 100 Hz electrical stimulation and (3) either CTAP or naltrindole (i.c.v.) almost completely blocked the antinociceptive effect induced by 2 Hz or 30 Hz electrical stimulation, but was less effective in blocking antinociception induced by 100 Hz electrical stimulation; nor-binaltorphimine (i.c.v.) greatly reduced antinociception induced by 30 Hz or 100 Hz electrical stimulation, but not by 2 Hz electrical stimulation. These results indicate that the antinociception induced by 2 Hz electrical stimulation is mediated by both mu and delta opioid receptors; the antinociception induced by 100 Hz electrical stimulation is mediated primarily by the kappa receptor; and the antinociception induced by 30 Hz electrical stimulation is mediated by all three opioid receptor types. Thus, the antinociceptive effect induced by peripheral electrical stimulation, as measured by the CWT, involves opioid receptors in the rat brain.
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J. Pharmacol. Exp. Ther. · May 1996
Physiological release of striatal acetylcholine in vivo: modulation by D1 and D2 dopamine receptor subtypes.
Our experiments assessed the modulation of striatal acetylcholine (ACh) output by dopamine (DA) receptor subtypes under physiological conditions using in vivo microdialysis in awake rats. The degree to which the dopaminergic modulation of striatal cholinergic neurons might vary as a function of local extracellular ACh level also was examined by application of varying concentrations of the acetylcholinesterase (AChE), inhibitor neostigmine (NEO) in the microdialysis perfusate. Under physiological conditions (O NEO), the amount of ACh in the dialysates was 25.1 +/- 2.2 fmol/20-microliters sample (n = 20) whereas values of 67.9 +/- 3.5 (n = 35) and 527.7 +/- 56.1 (n = 13) fmol/20-microliters sample were obtained when the applied NEO concentration was 10 and 100 nM, respectively. ⋯ Thus, under physiological or low NEO (10 nM) conditions a prevalent D2-mediated inhibition as well as an opposing D1-mediated excitation of striatal ACh output can be demonstrated. At a higher NEO concentration (100 nM), regulation of the striatal ACh system by DA receptor subtypes is differentially affected such that the D2-mediated inhibitory influence no longer predominates over the D1-mediated excitatory drive. Caution should be exercised when interpreting ACh efflux data obtained using microdialysis under conditions of AChE inhibition.