STUDIES ON MORPHINE. VI. INGESTION OF MORPHINE SOLUTIONS IN NORMAL MICE AND RATS AND IN ANIMALS WITH CHRONIC MORPHINISM.
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Behavior, Animal↗
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Forensic drug testing for opiates. II. Metabolism and excretion rate of morphine in humans after morphine administration.
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.
Adult↗
Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine.
Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i.v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i.v. infusion of morphine sulphate. Drugs were infused (135 microL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 mumol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-native rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 mumol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 mumol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Pharmacokinetic differences of morphine and morphine-glucuronides are reflected in locomotor activity.
The main metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been considered to participate in some of the effects of morphine. There is limited knowledge of the pharmacokinetics and dynamics of morphine and the main metabolites in mice, but mice are widely used to study both the analgesic effects and the psychomotor effects of morphine. The present study aimed to explore pharmacokinetic differences between morphine and morphine-glucuronides in mice after different routes of administration, and to investigate how possible differences were reflected in locomotor activity, a measure of psychostimulant properties. Mice were given morphine, M3G or M6G by different routes of administration. Serum concentrations versus time curves, pharmacokinetic parameters and locomotor activity were determined. Intraperitoneal administration of morphine reduced the bioavailability compared to intravenous and subcutaneous administration, but not so for morphine-glucuronides. The two morphine-glucuronides had similar pharmacokinetics, but morphine demonstrated higher volume of distribution and clearance than morphine-glucuronides. The present results demonstrated no locomotor effect of M3G, but a serum concentration effect relationship for morphine and M6G. When serum concentrations and effect changes were followed over time, there was some right hand shifts with respect to locomotor activity, especially during the declining phase of the concentration curve and particularly for M6G.
Animals↗
The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function.
Morphine-6-glucuronide is a metabolite of morphine that binds to the opioid receptor and is analgesic in animals and humans. Although accumulation of morphine-6-glucuronide in patients with renal insufficiency has been implicated in morphine toxicity, the contribution of the metabolite to morphine analgesia in patients with normal renal function has not been established. To evaluate this contribution, we repeatedly sampled blood and assessed effects during and after a loading infusion with morphine (mean duration, 168 minutes) in 14 patients with chronic pain, all of whom had normal serum creatinine levels. Plasma concentrations of morphine and morphine-6-glucuronide were assayed by use of high performance liquid chromatography with electrochemical detection. Patients were divided into three groups on the basis of the molar concentration ratio of morphine-6-glucuronide:morphine from the start of the infusion until 240 minutes later: Group 1 (n = 5) had a mean ratio greater than or equal to 0.7:1; group 2 (n = 4) had a mean ratio less than 0.7:1 but greater than or equal to 0.4:1; and group 3 (n = 5) had a mean ratio less than 0.4:1. Time-effect plots revealed that average and peak relief were greater in group 1 than group 2 and greater in group 2 than group 3. For all patients, mean morphine-6-glucuronide:morphine ratio throughout the study was significantly correlated with mean pain relief (r = 0.611, p less than 0.02). These data suggest that morphine-6-glucuronide contributes to morphine analgesia in patients with normal renal function. The role of the metabolite should be considered when morphine is used clinically.
Adult↗
Continued morphine modulation of calcium channel currents in acutely isolated locus coeruleus neurons from morphine-dependent rats.
1. The actions of the opioid agonists morphine and methionine-enkephalin (met-enkephalin) on the calcium channel currents (IBa) of acutely isolated locus coeruleus (LC) neurons from morphine-dependent and vehicle-treated rats were examined using whole cell patch clamp techniques. 2. In LC neurons maintained in 5 microM morphine, co-superfusion of naloxone (1 microM) or the mu-opioid receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 1 microM) with morphine resulted in a significant increase in the amplitude of IBa. The increases in IBa were not different in neurons from morphine-dependent or vehicle rats. The increase in IBa was mimicked by washing off morphine, but not by co-superfusion of the kappa-receptor antagonist norbinaltorphimine (300 nM) or the delta-receptor antagonist ICI-174864 (1 microM). 3. In spontaneously withdrawn LC neurons from morphine-dependent rats, met-enkephalin (pD2 7.1, maximum inhibition 49%) and morphine (pD2 6.5, maximum inhibition 33%), inhibited IBa in all cells. In cells from vehicle rats the pD2 for met-enkephalin was 7.3, maximum inhibition 52%, while the pD2 for morphine was 6.6 and the maximum inhibition 43% (P<0.05 versus cells from morphine-dependent rats). 4. IBa in LC neurons was mostly comprised of omega-conotoxin GVIA- (N-type) and omega-agatoxin IVA- (P/Q-type) sensitive components, with lesser amounts of nimodipine-sensitive current and current resistant to all three blockers. Neither the density of IBa nor the proportion of any of the components of IBa differed between neurons from morphine-dependent or vehicle-treated rats. 5. This study demonstrates that in morphine-dependent rats, morphine and met-enkephalin modulation of somatic IBa in LC neurons displays modest tolerance compared with untreated rats. Further, chronic morphine treatment does not alter the type or density of IBa in LC neurons. These results provide more evidence that functional mu-opioid receptor coupling is not dramatically altered in the LC in morphine-dependent rats.
Analgesics, Opioid↗
Clocinnamox distinguishes opioid agonists according to relative efficacy in normal and morphine-treated rats trained to discriminate morphine.
High doses of insurmountable antagonists or frequent administration of high doses of agonists are required to alter the potency of opioid agonists to produce discriminative stimuli. In the present study, insurmountable antagonism and repeated agonist treatment were combined to remove or disable a large enough proportion of mu-opioid receptors to alter the potency or maximal effect for four agonists in male Sprague-Dawley rats trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio 15 schedule of food reinforcement. All agonists produced 88 to 100% morphine responding and were differentially sensitive to clocinnamox antagonism (fentanyl < morphine < or = buprenorphine = nalbuphine). Repeated treatment with 20 mg/kg per day morphine for 6 days decreased by 2- to 3-fold the potency of fentanyl, morphine, and buprenorphine to produce morphine responding. After morphine treatment, 3.2 mg/kg clocinnamox produced a 7-fold further decrease in morphine potency. Clocinnamox (10 mg/kg) produced a 7- and 12-fold further decrease in morphine and fentanyl potency, respectively, a reduction in the slope of the morphine dose-response curve, and a suppression of the maximal morphine responding for buprenorphine. Repeated treatment with 10 mg/kg per day morphine for 6 days failed to alter the potency of nalbuphine to produce morphine responding. In these morphine-treated rats, doses of 3.2 or 10 mg/kg clocinnamox suppressed the maximal morphine responding. Taken together, these data indicate that combined insurmountable antagonist and repeated agonist treatment produce additive effects at mu-opioid receptors to diminish discriminative stimulus effects in a manner predicted by the relative efficacy of opioid agonists.
Algorithms↗
Systemic coadministration of chloramphenicol with intravenous but not intracerebroventricular morphine markedly increases morphine antinociception and delays development of antinociceptive tolerance in rats.
Chloramphenicol, an in vitro inhibitor of the glucuronidation of morphine to its putative antianalgesic metabolite, morphine-3-glucuronide (M3G), was coadministered with morphine in adult male Sprague-Dawley rats to determine whether it inhibited the in vivo metabolism of morphine to M3G, thereby enhancing morphine antinociception and/or delaying the development of antinociceptive tolerance. Parenteral chloramphenicol was given acutely (3-h studies) or chronically (48-h studies). Morphine was administered by the i.v. or i.c.v. route. Control rats received chloramphenicol and/or vehicle. Antinociception was quantified using the hotplate latency test. Coadministration of chloramphenicol with i.v. but not i.cv. morphine increased the extent and duration of morphine antinociception by approximately 5.5-fold relative to rats that received i.v. morphine alone. Thus, the mechanism through which chloramphenicol enhances i.v. morphine antinociception in the rat does not directly involve supraspinal opioid receptors. Acutely, parenteral coadministration of chloramphenicol and morphine resulted in an approximately 75% increase in the mean area under the serum morphine concentration-time curve but for chronic dosing there was no significant change in this curve, indicating that factors other than morphine concentrations contribute significantly to antinociception. Antinociceptive tolerance to morphine developed more slowly in rats coadministered chloramphenicol, consistent with our proposal that in vivo inhibition of M3G formation would result in increased antinociception and delayed development of tolerance. However, our data also indicate that chloramphenicol inhibited the biliary secretion of M3G. Whether chloramphenicol altered the passage of M3G and morphine across the blood-brain barrier remains to be investigated.
Analgesics, Opioid↗
Peripheral morphine analgesia: synergy with central sites and a target of morphine tolerance.
Morphine injected s.c. in the tail is a potent analgesic in the tail-flick assay when the radiant heat source is focused directly over the injection site (ED50, 4.5 micrograms), but not if the radiant heat source is moved 1 cm proximally or distally to the injection site. Naloxone given systemically reverses this peripheral analgesia. Antisense oligodeoxynucleotides directed against exons 1 and 4 of MOR-1, a cloned mu opioid receptor, administered intrathecally (i.t.) block the local analgesic effect of morphine in the tail, indicating that the local response is mediated through mu receptors located on the terminals of sensory neurons from the dorsal root ganglia. Combinations of morphine given locally in the tail and spinally (i.t.) are synergistic. Spinal morphine also synergizes with systemic morphine in analgesia assays. Supraspinal morphine enhances systemic morphine analgesia, but less dramatically. We also examined tolerance on these analgesic systems by using a daily morphine injection paradigm which shifts the dose-response curve for systemic morphine approximately 2-fold after 5 days. In this paradigm, morphine's analgesic potency after either supraspinal or spinal administration alone does not change. However, the dose-response curve for local morphine in the tail is shifted by over 19-fold. The analgesic activity of the combination of supraspinal and systemic morphine is lowered approximately 2-fold and the combination of i.t. and systemic morphine by 12-fold. These studies confirm the presence of a peripheral mechanism for morphine analgesia mediated by mu receptors located on sensory neurons from the dorsal root ganglia, which is extremely sensitive to chronic morphine dosing.
Analgesia↗
Effects of morphine, naltrexone, and dextrorphan in untreated and morphine-treated pigeons.
Six pigeons, trained to peck a response key on a fixed-ratio 20 schedule of food reinforcement, were used to examine the effects of morphine, naltrexone, and dextrorphan, before, during, and after chronic treatment with increasing doses of morphine (10.0-100.0 mg/kg/day). Tolerance developed to the rate-decreasing effect of the daily maintenance doses of morphine within 2 days of each dose increase. A small amount of tolerance to morphine and supersensitivity to naltrexone was evident within the 1st week of morphine treatment (10.0 mg/kg/day). Continued administration of morphine (32.0-100.0 mg/kg/day) produced further tolerance to morphine and supersensitivity to naltrexone, as evidenced by a 5-fold increase in the dose of morphine, and 1,000-fold decrease in the dose of naltrexone, necessary to suppress responding. By the 4th week of treatment (100.0 mg/kg/day), a modest tolerance had also developed to the rate-decreasing effects of dextrorphan. Suppression of responding by naltrexone, but not morphine or destrorphan, was accompanied by a loss in body weight over the 1- to 2-h session in morphine-maintained pigeons; both weight loss and reduced response rates also occurred on termination of morphine treatment. Sensitivity to the rate-decreasing effects of morphine and naltrexone was near normal within 10 days following termination of morphine treatment. The dramatic changes in sensitivity to naltrexone and morphine produced by daily morphine injections, as well as the ability to generate complete dose-effect curves within a single session, indicate that this behavioral preparation may provide sensitive concurrent measures of narcotic tolerance and supersensitivity to antagonists in the pigeon.
Animals↗
Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats.
To clarify the effects of withdrawal from chronic morphine treatment on cerebral dopamine (DA) turnover, we have measured the alpha-methyl-p-tyrosine (alpha MT)-induced depletion of DA in five brain areas of male Wistar rats given morphine twice daily for 40 or 60 days. After the last morphine dose (50 or 70 mg/kg) the rats were withdrawn for 1, 2 or 4 days. In order to study the development of tolerance some of the rats were challenged with 10 mg/kg of morphine. Withdrawal of morphine retarded the alpha MT-induced DA depletion in the limbic forebrain and after long enough chronic treatment in the striatum, too. The challenge dose of morphine accelerated the cerebral DA depletion slightly less in rats withdrawn for 1 day from 60-day chronic morphine treatment than in rats treated chronically with saline, but it enhanced the DA depletion more in rats withdrawn from morphine for 2 and 4 days than in chronic saline rats. This enhancement was clearest in rats withdrawn for 4 days from 60-day treatment. Thus withdrawal from morphine seems to sensitize the rats to the DA depletion accelerating effect of morphine. Our results show that repeated administration of morphine creates no marked tolerance to the DA depletion accelerating effect of morphine. In contrast, the dopaminergic neurones of the chronically treated rats seem to depend on continuous morphine administration for their normal functioning. Furthermore, the retarded DA turnover after discontinuation of morphine treatment seems to sensitize the dopaminergic neurones to the DA depletion accelerating effect of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations.
In earlier studies, it was shown that male rats were considerably more sensitive to the antinociceptive properties of morphine than females in several antinociceptive assays. The purpose of our studies was to examine whether these male-female differences might be due to differences in the blood and brain levels of morphine attained after its s.c. injection rather than to intrinsic differences in the central nervous system sensitivity to the drug. Our results confirmed that males were considerably more sensitive than females to the antinociceptive properties of morphine on the hot-plate test; the ED50 in males was approximately half that found in females. These sex differences were not unique to morphine because males were also more sensitive to the antinociceptive properties of the potent mu agonist, alfentanil. With respect to the pharmacokinetics of morphine, we found that there was a linear relationship in both males and females between the dose of morphine injected and the blood and brain levels achieved 60 min after the injection when the sex-linked differences in morphine-induced antinociception was greatest; no sex differences were found in the peak levels of morphine attained in blood or brain at any dose of morphine. Furthermore, there were no sex-linked differences in the elimination half-life of morphine from blood and, similarly, there were no differences in the disappearance of morphine from brain. On the basis of these data, it appears that the sex-related differences we have observed between males and females in the response to morphine's antinociceptive activity cannot be explained by differences in the pharmacokinetics of morphine. Rather, it appears that sex differences in morphine-induced antinociception are related to inherent differences in the sensitivity of the brain to morphine.
Alfentanil↗
Acute tolerance to spinally administered morphine compares mechanistically with chronically induced morphine tolerance.
The mechanistic similarity between acutely and chronically induced morphine tolerance has been previously proposed but remains largely unexplored. Our experiments examined the modulation of acutely induced tolerance to spinally administered morphine by agonists that affect the N-methyl-D-aspartate receptor and nitric oxide synthase systems. Antinociception was detected via the hot water (52.5 degrees C) tail flick test in mice. Intrathecal pretreatment with morphine (40 nmol) produced a 9.6-fold rightward shift in the morphine dose-response curve. This shift confirmed the induction of acute spinal morphine tolerance. Intrathecal copretreatment with the receptor antagonists (competitive and noncompetitive, respectively) dizolcipine (MK801, 3 nmol) or LY235959 (4 pmol) and morphine [40 nmol, intrathecally (i.t.)] attenuated acute tolerance to morphine measured 8 hr later. A 60-min pretreatment of 7-nitroindazole (6 nmol, i.t.), a selective neuronal NOS inhibitor, followed by administration of morphine (40 nmol, i.t.) blocked the induction of morphine tolerance. Intrathecal copretreatment with morphine (40 nmol, i.t.) and agmatine (4 nmol, i.t.), an imidazoline, receptor agonist and putative nitric oxide synthase inhibitor, almost completely abolished acute spinal morphine tolerance. The results of these experiments agree with previous reports using models of chronically induced morphine tolerance. This evidence supports the proposal that the mechanisms responsible for acute morphine tolerance parallel those underlying chronic morphine tolerance. This study attests to the powerful predictive value of acute induction as a model for morphine tolerance.
Agmatine↗
Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration.
There is growing evidence that renally-impaired patients receiving morphine therapy are at greater risk of developing opiate toxicity, due to the accumulation of an active metabolite, morphine-6-glucuronide (M6G), which is usually excreted by the kidneys. This study examined the relationships between morphine dosage, renal function, and trough plasma concentrations of morphine and its glucuronide metabolites in 21 patients (aged mean: 68.5 years: 11 males) receiving either oral or subcutaneous morphine for terminal cancer pain. The median daily morphine dosages (mg.kg-1) were: orally 1.87 (range 0.37-6.82) and subcutaneously 1.64 (range 0.22-3.60). The median plasma concentrations of morphine, morphine-3-glucuronide (M3G), and M6G (ng.ml-1) were: 36.0, 1035.2, and 142.3, respectively. The plasma concentrations of morphine, M3G and M6G were each significantly related to the daily morphine dosage (n = 21, Spearman r = 0.79, 0.91, and 0.88 respectively). Accumulation of the morphine glucuronides was dependent on renal function. The plasma concentrations of M3G and M6G, when divided by the morphine concentration, were significantly related to the calculated creatinine clearance of the patient. Patients receiving oral morphine had higher plasma concentration ratios of glucuronide/morphine than those receiving subcutaneous therapy, presumably due to first-pass glucuronidation. The results of this study confirm that accumulation of the pharmacologically active M6G is related to renal function, which probably explains the observation that morphine dosage requirements are generally reduced in patients with renal impairment.
Aged↗
Effects of denervation on the sensitizing effect to noradrenaline induced by morphine in the vas deferens of mice treated chronically with morphine.
The acute administration of morphine to the isolated vas deferens from mice chronically exposed to this analgesic, induced a facilitatory effect on the responses of the muscle to exogenous noradrenaline. It has been suggested that this sensitizing property of morphine might reflect a dependence-like state of the vas deferens. In the present paper, the capability of met- and leu-enkephalin to substitute for morphine was studied, as well as the influence of innervation on the apparent dependence state. The contractile responses to noradrenaline and to acetylcholine were increased after the administration of morphine to the bath containing a denervated vas deferences, prepared from chronically morphinized mice. Morphine administration facilitated noradrenaline- but not acetylcholine-induced contractile effects in vas deferens isolated from mice which had been chronically treated with either morphine or morphine plus guanethidine. The presence of met- or leu-enkephalin in the isolated vas deferens from chronically morphinized mice (either intact, denervated or treated with guanethidine) failed to sensitize contractile responses to noradrenaline or acetylcholine. It is concluded that (a) the sensitizing effect induced by morphine in the vas deferens from mice chronically treated with morphine is specific for the adrenergic neurotransmitter; (b) the effect of morphine is not mimicked by opiate peptides; and (c) denervation of the vas deferens of mice treated chronically with morphine does not suppress the noradrenaline-sensitizing property of morphine.
Acetylcholine↗
Effect of prior morphine-3-glucuronide exposure on morphine disposition and antinociception.
Morphine-3-glucuronide (M3G), the primary metabolite of morphine in humans and rats, has been reported to antagonize morphine-induced pharmacologic effects. The present experiment was conducted to evaluate the effect of prior systemic M3G exposure on morphine disposition and antinociceptive response in male Sprague-Dawley rats. Saline (N = 6), low dose M3G (0.15 mg/hr, N = 7), or high dose M3G (0.30 mg/hr, N = 6) was infused for 720 min prior to the administration of morphine by i.v. bolus (2 mg/kg). Tail-flick latencies in response to hot water (50 degrees) were assessed prior to and for 180 min after the morphine test dose. M3G exposure had no significant effect on morphine pharmacokinetics, although a disproportionate increase in M3G concentrations was observed following the morphine i.v. bolus dose in rats infused with high dose M3G. Morphine-induced antinociception, expressed as the percent of maximum response (%MPR), was maximum 15 min after morphine administration and returned to baseline by 180 min. A pharmacokinetic-pharmacodynamic model was constructed to relate tail-flick latencies to morphine serum concentrations. In saline-exposed rats, the antinociceptive response to morphine was characterized by a sigmoidal Emax model, with an EC50 of 328 ng/mL, a Hill coefficient (gamma) of 4.5, and a half-life for the offset of pharmacologic effect of 11 min. No statistically significant differences in the intensity or duration of morphine-induced response were detected between saline- and M3G-exposed animals. These results suggest that systemic formation of M3G is unlikely to contribute significantly to the development of tolerance to morphine antinociception.
Animals↗
The effect of old age on the disposition and antinociceptive response of morphine and morphine-6 beta-glucuronide in the rat.
The aims of this study were to examine the effect of old age on the pharmacokinetics of morphine and morphine-6 beta-glucuronide (M6G) and their relationships to antinociceptive activity. Morphine (21.0 mumol/kg) or M6G (21.7 mumol/kg) were administered s.c. to young adult and aged male Hooded-Wistar rats. Antinociceptive effect was measured by the tail-flick method at various times up to 2.5 h or 6.5 h after morphine or M6G administration, respectively, and concentrations of morphine, morphine-3 beta-glucuronide (M3G) and M6G in plasma and brain were determined by HPLC. Creatinine clearance was significantly lower by 33% or 21% in aged compared to young adult rats receiving morphine or M6G, respectively. After morphine administration, the areas under the (i) antinociceptive effect-time curve, (ii) plasma morphine concentration-time curve, and (iii) brain morphine concentration-time curve were not different between young adult and aged rats. However, the AUC for plasma M3G was five-fold higher in the aged relative to young adult rats, which could not be accounted for by only a 33% lower creatinine clearance. M6G was not detected in any plasma or brain sample from rats administered morphine and no M3G was detected in brain. For M6G administration, the areas under the (i) antinociceptive effect-time curve, and (ii) plasma M6G concentration-time curve were 1.8- and 1.6-fold higher in aged compared to young adult rats, respectively. Concentrations of M6G in brain were below the limit of quantification. No morphine or M3G was detected in any of the plasma or brain samples of rats administered M6G. The results demonstrate no change in morphine antinociception and pharmacokinetics with age, and suggest that blood-brain barrier permeability and reception sensitivity to morphine are not altered in aged rats. Accumulation of M3G in plasma of aged rats is probably due to diminished renal clearance of M3G in addition to a reduction in the biliary excretion of M3G. The heightened sensitivity of the aged rats to M6G is probably due to the observed altered kinetics of M6G rather than a pharmacodynamic change.
Aging↗
Disposition and analgesic effects of systemic morphine, morphine-6-glucuronide and normorphine in rat.
Morphine, morphine-6-glucuronide and normorphine were administered to male Sprague-Dawley-rats. Analgesic effect was estimated with the hot plate and spinal nociceptive reflex depression. After intraperitoneal administration the molar potency ratio of morphine-6-glucuronide/morphine was 1.7 estimated by the paw lick latency on the hot plate utilizing a linked pharmacokinetic-pharmacodynamic model. The potency ratio of morphine-6-glucuronide/morphine utilizing the spinal nociceptive reflex depression after intravenous administration was estimated to be within the earlier reported range of 1-4 after systemic administration of the drugs. In contrast to what is seen in man virtually no morphine-6-glucuronide was formed in Sprague-Dawley rats after administration of morphine, much lower levels of morphine-3-glucuronide were also seen. The molar AUC ratio of morphine-3-glucuronide/morphine was 1.8 +/- 0.5 and the corresponding ratio for normorphine/morphine was 0.2 +/- 0.06. After intraperitoneal administration of morphine, morphine-6-glucuronide and normorphine mean systemic clearance values of 413 +/- 95, 50 +/- 11 and 187 +/- 54 ml.min.kg-1 respectively were observed. Varea was 9.0 +/- 2.1, 0.8 +/- 0.2 and 4.9 +/- 1.4 L.kg-1 respectively. The slow absorption of morphine-6-glucuronide was illustrated by the mean Tmax-value of the 16 min. as compared with 9 min. for morphine and 10 min. for normorphine. It was possible to fit pharmacokinetic and pharmacodynamic data of behavioural analgesic effect of both morphine and morphine-6-glucuronide to a parametric model linking the sigmoid Emax model to standard pharmacokinetic equations.
Analgesics, Opioid↗