Abstract
The development of tolerance to the depressant and stimulant actions of morphine on locomotor activity and brain acetylcholine (ACh) utilization (indirect turnover) was investigated in the rat. When administered to nontolerant rats, 1.0 mg/kg s.c. of morphine produced an increase in locomotor activity and a concomitant increase in ACh utilization. Larger doses produced biphasic effects on locomotor activity, but only 10 mg/kg s.c. resulted in both an initial decrease and subsequent increase in ACh utilization in whole rat brain. The depressant and stimulant actions of morphine on both endpoints were antagonized by 1.0 mg/kg i.p. of naloxone administered 30 min before the maximum effect. Tolerance to morphine was produced by t.i.d. injections of increasing doses. Rapid tolerance developed to the locomotor depressant actions of morphine and to the decrease in brain ACh utilization. Tolerance to the depressant effects resulted in an enhanced stimulant action. Tolerance also developed to the stimulant actions of morphine but only when large doses of drug were administered daily. Biphasic effects of 10 mg/kg of morphine on brain ACh utilization were also observed in the hippocampus, thalamus and hypothalamus. Only a decrease in ACh utilization was observed in the caudate nucleus. Tolerance developed to the decreases and increases in ACh utilization in these discrete brain regions. This study demonstrates that tolerance development to the depressant and stimulant actions of morphine is complex and involves different dose and time schedules. It is not possible therefore to study tolerance to the actions of morphine without specifying the precise endpoint studied and the tolerance schedule utilized.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 848-858 |
| Number of pages | 11 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 207 |
| Issue number | 3 |
| State | Published - 1978 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Tolerance development to the biphasic effects of morphine on locomotor activity and brain acetylcholine in the rat. / Vasko, Michael; Domino, E. F.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 207, No. 3, 1978, p. 848-858.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tolerance development to the biphasic effects of morphine on locomotor activity and brain acetylcholine in the rat
AU - Vasko, Michael
AU - Domino, E. F.
PY - 1978
Y1 - 1978
N2 - The development of tolerance to the depressant and stimulant actions of morphine on locomotor activity and brain acetylcholine (ACh) utilization (indirect turnover) was investigated in the rat. When administered to nontolerant rats, 1.0 mg/kg s.c. of morphine produced an increase in locomotor activity and a concomitant increase in ACh utilization. Larger doses produced biphasic effects on locomotor activity, but only 10 mg/kg s.c. resulted in both an initial decrease and subsequent increase in ACh utilization in whole rat brain. The depressant and stimulant actions of morphine on both endpoints were antagonized by 1.0 mg/kg i.p. of naloxone administered 30 min before the maximum effect. Tolerance to morphine was produced by t.i.d. injections of increasing doses. Rapid tolerance developed to the locomotor depressant actions of morphine and to the decrease in brain ACh utilization. Tolerance to the depressant effects resulted in an enhanced stimulant action. Tolerance also developed to the stimulant actions of morphine but only when large doses of drug were administered daily. Biphasic effects of 10 mg/kg of morphine on brain ACh utilization were also observed in the hippocampus, thalamus and hypothalamus. Only a decrease in ACh utilization was observed in the caudate nucleus. Tolerance developed to the decreases and increases in ACh utilization in these discrete brain regions. This study demonstrates that tolerance development to the depressant and stimulant actions of morphine is complex and involves different dose and time schedules. It is not possible therefore to study tolerance to the actions of morphine without specifying the precise endpoint studied and the tolerance schedule utilized.
AB - The development of tolerance to the depressant and stimulant actions of morphine on locomotor activity and brain acetylcholine (ACh) utilization (indirect turnover) was investigated in the rat. When administered to nontolerant rats, 1.0 mg/kg s.c. of morphine produced an increase in locomotor activity and a concomitant increase in ACh utilization. Larger doses produced biphasic effects on locomotor activity, but only 10 mg/kg s.c. resulted in both an initial decrease and subsequent increase in ACh utilization in whole rat brain. The depressant and stimulant actions of morphine on both endpoints were antagonized by 1.0 mg/kg i.p. of naloxone administered 30 min before the maximum effect. Tolerance to morphine was produced by t.i.d. injections of increasing doses. Rapid tolerance developed to the locomotor depressant actions of morphine and to the decrease in brain ACh utilization. Tolerance to the depressant effects resulted in an enhanced stimulant action. Tolerance also developed to the stimulant actions of morphine but only when large doses of drug were administered daily. Biphasic effects of 10 mg/kg of morphine on brain ACh utilization were also observed in the hippocampus, thalamus and hypothalamus. Only a decrease in ACh utilization was observed in the caudate nucleus. Tolerance developed to the decreases and increases in ACh utilization in these discrete brain regions. This study demonstrates that tolerance development to the depressant and stimulant actions of morphine is complex and involves different dose and time schedules. It is not possible therefore to study tolerance to the actions of morphine without specifying the precise endpoint studied and the tolerance schedule utilized.
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M3 - Article
C2 - 731435
AN - SCOPUS:0018245215
VL - 207
SP - 848
EP - 858
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -