Perinatal morphine II: Changes in cortical plasticity
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Abstract We have previously shown that perinatal exposure to morphine impairs reactive plasticity of serotonin (5‐HT) neurons following selective neonatal lesion (Gorio et al., J Neurosci Res 34:462–471, 1993). This study shows that morphine inhibits also that the compensatory sprouting of intact axons after partial denervation. Neonatal 6‐OHDA injection causes norepinephrine (NE) depletion in the frontal cortex, which triggers a compensatory increase of dopamine, serotonin (5‐HT), and met‐enkephalin content correlated by the increased density of tyrosine hydroxylase– and 5‐HT–positive axons. In perinatal morphine‐treated rats, no compensatory changes are observed after neonatal 6‐OHDA depletion of NE in the frontal cortex. ©1995 Wiley‐Liss, Inc.Transcranial Direct Current Stimulation
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Indentation
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Physical dependence
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Abstract Results of a number of studies on the development of tolerance to morphine suggest that at least some aspects of this tolerance are immunologic-like in character (for reviews see Friedler (1) and Cochin (2)). Evidence that the morphine configuration is immunogenic is provided by Ryan et al. (3) who recently reported the apparent presence of antibody against morphine in the sera of approximately 40% of heroin addicts studied. Preliminary findings from our laboratory, in studies reported here, have indicated that in the rabbit prolonged exposure to morphine is associated with an increase in serum binding of 14C-labeled morphine, both after withdrawal from morphine and after a brief re-exposure to morphine. Two albino New Zealand female rabbits were given multiple doses of morphine sulfate or morphine hydrochloride (Merck, USP) administered subcutaneously in three courses of injections spaced 1 and 2 months apart.
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Urine levels of free and total morphine were determined by GC/MS for four male subjects who received single doses of 20 mg of morphine sulfate intramuscularly. Peak concentrations were observed within 10 h for both conjugated and free morphine; thereafter, levels declined rapidly. Initially, free morphine represented from 25 to 34% of the total amount of morphine present, but this ratio declined after 12 h to an average of only 5.9% of total morphine. Free morphine accounted for an overall mean of 6.8% of the dose excreted in urine and conjugated morphine for 58.6%. The mean excretion half-life for free morphine was 6.6 h and for conjugated morphine was 8.2 h. The lower concentration and shorter half-life of free morphine resulted in a shorter detection time for free morphine versus total morphine at a 300-ng/mL cutoff. An equivalent detection time for free morphine was obtained when its cutoff was lowered to 25 ng/mL. The possibility that morphine is metabolized to codeine was unequivocally ruled out by the finding of an absence of codeine at or above the LOD of the GC/MS assay in all clinical specimens collected after morphine administration.
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Drug tolerance
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著者らは先の実験でnaiveラットにmorphine混入飼料を2つの容器に入れて0.5 mg/g vs. 1mg/gの割合で与えると, 2週間以上の強制適用期間以降からmorphineの高濃度 (1mg/g) 側の摂取率が漸次増加していく現象はmorphineのpositive reinforcement にもとずくと報告した.今回, 個別ケージにmorphine vs. quinineあるいはmorphine vs. quinine vs.普通飼料の条件下でmorphineの選択的摂取率の経日変化を検討した.実験動物はSD系ラット, 5～7週令, 1群6～9匹としてnaiveラットとmorphine経験ラットを用いた.Naiveラットにmorphine (0.5mg/g) vs. quinine (0.5mg/g) 条件下24時間自由摂取させると, morphineの自発的摂取率 (M-SIR) は初日17% (10mg/kg/day) から漸次増加し, 3週間後には77% (30mg/kg/day) に達した.またmorphine (1mg/g) vs. quinine (1mg/g) の場合, 低用量群同様に漸次M-SIRは増加するが, 2週間目までのMSIRの増加が急速であった.したがって1日のmorphine摂取量が10mg/kg/dayから50～60mg/kg/dayの用量範囲内においてはmorphineのpositive reinforcerとしての効果がdose-dependentにみられた.注射によるmorphine経験ラットおよびmorphine混入1司料による依存あるいは経験ラットの場合, naiveラット同様にM-SIRは漸次増加するが, 特異的に初期4日間著明に高いM-SIRを示した.また強制適用後休薬しないでただちに選択摂取させると, 3～4日目にnaiveラットあるいは経験ラットが3週間目に達した70～80%の摂取率を示し, 以後そのレベルを維持した.さらにその時点での1日のmorphine摂取量は強制適用期間中の平均摂取量とほぼ等しかったことからラットはmorphineの実質的必要量を自発的に維持することを示唆する.本実験からmorphineの精神依存能の一面をラットでのmorphineの選択的摂取行動から推察し, morphine嗜好は休薬後もsecondary abstinence syndromeとして長く持続することを認めた.
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Morphine administered simultaneously to intracerebroventricular (i.c.v.) and intrathecal (i.t.) sites exhibits synergism, with the antinociceptive potency much greater than would be predicted from a simple addition of the potencies of the same dose administered to either site alone. This synergism was quantified in mice using both a fixed dose method, in which the morphine dose at one site was fixed while the AD50 (antinociceptive dose at 50% effectiveness) of morphine at the other site was determined; and a variable dose method, in which different doses of morphine were administered simultaneously to both sites at a fixed ratio, and the AD50 determined and compared to the AD50 at a single site alone. When animals were made tolerant to morphine by implantation of a 75-mg morphine pellet for 3 days, this synergism was eliminated, so that morphine administered simultaneously to i.c.v. and i.t. sites had an additive effect. However, administration of the peptide DynorphinA-(2-17) i.v. simultaneously to the test doses of morphine in morphine-tolerant animals resulted in a partial restoration of synergism. These results suggest that morphine-induced antinociception is highly dependent on an intact integrated central nervous system system and that the initial tolerance development is the result of a disruption of synergism between the central nervous system sites. Morphine tolerance results not from a reduced sensitivity to morphine at discrete central nervous system sites, but rather from a reduced synergistic interaction of morphine at spinal and supraspinal sites. In support of this conclusion, there was no tolerance observed in morphine-pelleted animals to morphine administered to i.c.v. or i.t. sites alone. DynorphinA-(2-17), a nonopioid peptide has previously been shown to enhance the antinociceptive potency of morphine in morphine-tolerant animals, appears to act by restoring this synergism.
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1. In rats injected repeatedly with a mixture of morphine and N-allylnormorphine in which the dose of the latter is too small to inhibit the analgesic effect of the morphine completely, the analgesic effect of the mixture declines more rapidly than it does to morphine alone. 2. It is demonstrated that this result is not due to tolerance to morphine, but to the greater inhibiting effect of N-allylnormorphine on morphine in partially tolerant than in non-tolerant rats. 3. Rats injected chronically with a morphine N-allylnormorphine mixture are less tolerant to morphine than are those injected for an equal length of time with morphine alone. 4. Rats injected chronically with N-allylnormorphine alone are more responsive to morphine than are normal animals.
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