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J M Fujimoto

Publications and source records attributed to J M Fujimoto.

At least 73 records · Page 4Linked to original sources
PubMed1985

Release of immunoreactive Met-enkephalin from the spinal cord by intraventricular beta-endorphin but not morphine in anesthetized rats.

Effect of beta-endorphin and morphine injected intraventricularly on the release of immunoreactive Met-enkephalin, Leu-enkephalin and dynorphin1-13 from the spinal cord was studied in anesthetized rats. Intraventricular beta-endorphin, 16 micrograms, caused a marked spinal release of immunoreactive Met-enkephalin and to a much lesser extent, of immunoreactive Leu-enkephalin while intraventricular morphine, 40 micrograms, did not cause any significant release of immunoreactive enkephalins. The release of immunoreactive Met-enkephalin was not blocked by the pretreatment with 5 mg/kg naloxone, i.p. Immunoreactive dynorphin1-13 was not released by either beta-endorphin or morphine. High performance liquid chromatographic analysis indicated that immunoreactive Met-enkephalin released by beta-endorphin had a retention time identical to [3H]Met-enkephalin. These findings in conjunction with previous pharmacological studies suggest different modes of pharmacological action for beta-endorphin and morphine.

Animals↗
PubMed1985

Unidirectional non-cross-tolerance (UNCT) in rats and an apparent dissociation between narcotic tolerance and physical dependence.

The phenomenon of unidirectional non-cross tolerance (UNCT) to etorphine was observed in adult male rats tolerant to morphine. Using a morphine pellet (four 75 mg morphine pellets) implantation protocol, a 10-fold increase in the analgesic ED50 value, obtained by tail-flick assay, was observed for morphine sulfate, with no alteration in analgesic ED50 value for etorphine. After etorphine pellet (two 60 micrograms pellets) implantation, no significant change in the ED50 value for etorphine was observed, but the ED50 value for morphine increased 15-fold. Both morphine and etorphine pellet-implanted animals, challenged with naloxone, showed similar qualitative signs of precipitated withdrawal. This seeming dissociation obtained by demonstration of physical dependence in the absence of tolerance to etorphine has its basis in the UNCT phenomenon. Thus, appropriate experimental paradigms must be included when evaluating tolerance to avoid specious conclusions.

Analgesia↗
PubMed1985

Analgesic potencies of morphine 3- and 6-sulfates after intracerebroventricular administration in mice: relationship to structural characteristics defined by mass spectrometry and nuclear magnetic resonance.

Morphine 3-sulfate, which carries a polar, acidic group at the 3-position much like morphine, does not differ greatly in analgesic potency from morphine following intracerebroventricular administration. This differs from the non-ionizable 3-methyl and 3-ethyl ethers, which are less potent analgesics than morphine. Morphine 6-sulfate, which differs from morphine by having an ionizable group at carbon-6 at physiological pH, is a more potent analgesic than morphine following intracerebroventricular administration. Variations in analgesic potency following modifications at the hydroxyl groups appear only to reflect alterations in point charges rather than structural alterations.

Analgesics↗
PubMed1985

Differential actions of intrathecal naloxone on blocking the tail-flick inhibition induced by intraventricular beta-endorphin and morphine in rats.

In the present study, it is proposed that the opioids applied to supraspinal brain sites produced their analgesic effects by the activation of different descending pain inhibitory systems. The blockade of the spinal endorphinergic system by intrathecal naloxone on the production of tail-flick inhibition induced by intraventricular beta-endorphin and morphine was then studied. Intraventricular injection of beta-endorphin and morphine produced an inhibition of the tail-flick response to the heat stimulus in rats. Intrathecal injection of naloxone at doses of 0.4 to 40 micrograms caused a dose-related blockade of the inhibition of the tail-flick response induced by intraventricular injection of beta-endorphin, and a high dose of naloxone (40 micrograms) completely blocked the tail-flick inhibition induced by intraventricular beta-endorphin (16 micrograms). On the other hand, intrathecal naloxone (12-120 micrograms) had only a very weak effect on the tail-flick inhibition induced by intraventricular morphine (40 micrograms). Intraventricular injection of naloxone at doses of 1.2 to 12 micrograms equally antagonized in a dose-dependent manner the tail-flick inhibition induced by intraventricular beta-endorphin and morphine. The results indicate that a spinal naloxone-sensitive endorphinergic system is involved in the production of beta-endorphin but not morphine-induced tail-flick inhibition, and suggest that intraventricular beta-endorphin and morphine elicit their pharmacological actions via the activation of different descending pain inhibitory systems; descending epsilon and mu systems for beta-endorphin and morphine, respectively, are proposed.

Analgesia↗
PubMed1984

Tolerance to morphine analgesia: decreased multiplicative interaction between spinal and supraspinal sites.

Mice injected with morphine at both a supraspinal (intracerebroventricular) and a spinal (intrathecal) site showed a multiplicative interaction between sites for the tail-flick analgesic response. In morphine pellet-implanted mice, the decrease in this interaction was the source of tolerance developed to subcutaneous morphine whereas the separate sites showed no tolerance. During morphine withdrawal (after removal of the morphine pellet) synergism between sites returned but the separate sites showed development of tolerance.

Analgesia↗
PubMed1984

Effect of intrabiliary administration of Triton X-100 on biliary excretory function in the rat.

Intrabiliary administration of Triton X-100 is of interest in producing effects on biliary tree permeability and canalicular biliary excretory function. Treatment with 0.4% Triton (40 microliter) was shown to increase the biliary excretion of intraportally administered [3H]sucrose. It also decreased recovery of [3H]sucrose given into the biliary tree. Thus, we concluded that Triton treatment increased biliary tree permeability. Using a different set of marker compounds, canalicular transport of bromphenol blue, [14C]morphine glucuronide and [3H]ouabain was found to be decreased. The fact that [3H] taurocholate excretion into bile was not affected whereas that of [3H]ouabain was lends support to the concept that taurocholate and ouabain are not transported by a common pathway.

Animals↗
PubMed1984

Evidence that spinal endorphin mediates intraventricular beta-endorphin-induced tail flick inhibition and catalepsy.

Naloxone injected intrathecally had a different effect on the inhibition of the inhibition of the tail flick response produced by beta-endorphin and morphine injected intraventricularly. The intrathecal naloxone completely antagonized the effect of beta-endorphin but had only a very weak effect on morphine. In the same rats the cataleptic response to beta-endorphin was antagonized as well; however no definitive conclusion could be made regarding the antagonism of the morphine-induced catalepsy. The results indicate that spinal endorphin is involved in the production of intraventricular beta-endorphin-induced spinal tail flick inhibition and suggest that intraventricular beta-endorphin and morphine elicit their pharmacological action via the activation of different descending inhibitory systems.

Animals↗
PubMed1984

Cadmium induced hypothermia in mice: dose dependent tolerance development.

The i.p. injection of Cd in mice will produce a dose related hypothermic response. The Cd appears to make the animals poikilothermic and their body temperature will approach the ambient temperature at which they are housed. The cause for this hypothermic action of Cd is not known, but we have demonstrated in our experiments that the effect may be partially related to a direct effect within the brain. In addition, the repeated injection of a low Cd dose (0.62 mg/kg) i.p. once daily for 3 days results in a profound tolerance to the Cd. A high dose (1.25 mg/kg i.p. once daily X 3 days) of Cd did not result in a similar tolerance phenomenon and a single injection of the high Cd dose 120 hr prior to the repeated low Cd dose regimen resulted in an obtunded tolerance response to the low dose. We propose that the higher Cd dose may have damaged the blood-brain barrier and this could account for the results we have observed.

Animals↗
PubMed1984

Morphine-morphine glucuronide pools in the rat liver: effects of Triton X-100.

The purpose was to determine the effect on the morphine-morphine glucuronide systems of Triton X-100 instilled into the area of the hepatic canalicular membrane by segmented retrograde intrabiliary injection (40 microliters of 0.4% Triton + 31 microliters of saline) in the isolated in situ perfused livers of male Sprague-Dawley rats. In all experiments, [14C]morphine was given by segmented retrograde intrabiliary injection (40 microliters of [14C]morphine + 110 microliters of saline). The control single pass perfusate contained 15.8% [14C]morphine glucuronide (MG) and 6.2% [14C]morphine. With Triton, the major changes observed were an unusual plateau-like pattern of egress of the [14C]MG into the perfusate and a profound decrease in the [14C]MG excretion into bile. In controls, 45 mg of unlabeled morphine sulfate intraportally 5 min before the [14C]morphine reduced the perfusate [14C]MG and increased [14C]morphine as expected by isotope dilution. Also, [14C]MG recovery in bile was accordingly decreased (intact pentobarbital-anesthetized rat); however, the [14C]morphine in bile did not change even though intracellular availability of [14C]morphine must have been increased. In pulse chase experiments, [14C] morphine was followed in 2 min with 45 mg of morphine sulfate intraportally. The perfusate [14C]MG declined and [14C]morphine increased. However, on the canalicular side (intact pentobarbital-anesthetized rat) no isotope dilution was evident: [14C]MG and [14C]morphine content in bile was similar to controls given no morphine sulfate. Triton treatment decreased the amount of [14C] morphine which could be chased into the perfusate. Several different pools of morphine and MG exist in the liver; the canalicular and sinusoidal sites respond very differently to manipulation of these pools.

Animals↗
PubMed1983

Differential tolerance to the intestinal inhibitory effect of opiates in mice.

The occurrence of unidirectional noncross-tolerance to heroin and etorphine induced antinociception in morphine tolerant mice prompted this study to determine whether this phenomenon occurs for opiate induced inhibition of intestinal transit. Tolerance to the intestinal inhibitory effect (charcoal meal test) of s.c. morphine, etorphine and heroin was reflected by an increase in the ED50 value and in most cases, a flattening of the dose response curve in morphine and etorphine pelleted mice (tested with pellet in place). A similar response was noted following intracerebroventricular administration of these agents in morphine pelleted mice. More tolerance developed to the relatively hydrophilic compound morphine than to the lipophilic compounds etorphine and heroin. Factors related to hydrophilicity and lipophilicity may be involved in the development of tolerance to opiates in the intestine although unidirectional non cross-tolerance did not occur.

Animals↗
PubMed1983

Effect of colchicine and S,S,S-tributyl phosphorotrithioate (DEF) on the biliary excretion of sucrose, mannitol and horseradish peroxidase in the rat.

The purpose of this study was to demonstrate the effect of colchicine and S,S,S-tributyl phosphorotrithioate (DEF) on vesicular transport of horseradish peroxidase (HRP) into bile at the same time that permeability changes occur in the canalicular membrane. Anesthetized Sprague-Dawley rats were surgically prepared with a bile duct cannulae. Four hours after colchicine pretreatment (10 mg/kg, i.p.), biliary excretion of intravenously injected sucrose and mannitol was increased, while that of HRP was decreased. Administration of these marker compounds from the bile side by segmented retrograde intrabiliary injection (SRII) (40 microliters washed in the 110 microliters saline) resulted in decreased biliary excretion of all three markers in colchicine-pretreated rats. Twenty minutes after DEF pretreatment by intrabiliary administration (40 microliters of DEF washed in with 31 microliters of saline and held in place for 0.5 min), the biliary excretion of intravenously injected sucrose and mannitol was decreased but that of HRP was increased; when administered by SRII, the biliary excretion of all three marker compounds was increased. These results demonstrate that colchicine, in addition to having blocked vesicular transport (HRP), also increased canalicular permeability to sucrose and mannitol. DEF, on the other hand, decreased canalicular permeability to sucrose and mannitol and enhanced vesicular transport of HRP.

Animals↗
PubMed1983

Inhibition of tail-flick and shaking responses by intrathecal and intraventricular D-Ala2-D-Leu5-enkephalin and beta-endorphin in anesthetized rats.

The present study compares the potencies of D-Ala2-D-Leu5-enkephalin (DADL) and beta-endorphin (beta-EP) injection intrathecally and i.c.v. on the inhibition of tail-flick and ice water-induced shaking responses in pentobarbital-anesthetized rats. Peptides were injected stereotaxically into the third ventricle or into the spinal subarachnoid space. The tail-flick response was measured 10 or 20 min after the injection of DADL or beta-EP, respectively, after which the rats were immersed for 5 min in ice water and the number of shakes was counted. Intrathecal DADL and beta-EP were equipotent in inhibiting both the tail-flick and shaking responses. However, treatment with naloxone (2 mg/kg i.p.) shifted the dose-response curve for both responses to the right more for the beta-EP than for DADL. Unlike the equipotency intrathecally, DADL by i.c.v. injection was less potent than beta-EP in inhibiting both the tail-flick and shaking responses. Previous results in the unanesthetized rat had also shown that i.c.v. DADL was less potent than beta-EP in inhibiting the tail-flick response. Thus, the spinal cord is sensitive to both DADL and beta-EP, whereas the supraspinal area is more sensitive to beta-EP. Also, because the potency of i.c.v. beta-EP for inhibiting tail-flick but not shaking was substantially reduced in anesthetized compared to unanesthetized rats, the neuronal substrates involved in inhibition of shaking are different from those of inhibition of the tail-flick. The differential sensitivities to i.c.v. vs. intrathecal administration and the unequal responses to the antagonistic action of naloxone indicate that DADL and beta-EP produce their action through different opioid receptors.

Analgesics↗
PubMed1983

Withdrawal tolerance and unidirectional non-cross-tolerance in narcotic pellet-implanted mice.

Analgesic ED50 values were determined for s.c. morphine, etorphine, heroin and methadone in mice implanted for 3 days with etorphine pellets. Tolerance to morphine (9-fold) was greater than to the other agents (2- to 4-fold). These results agreed with the previously reported unidirectional non-cross-tolerance effect seen after morphine pellet implantation where tolerance to the hydrophilic agent (morphine) was greater than for the more lipophilic agents (etorphine and heroin). As greater tolerance was found to s.c. morphine than for i.c.v. morphine, this manifestation of tolerance was described as a dispositional tolerance. Experimentally, we were able to observe two additional manifestations of tolerance. After pellet removal, the ED50 values for s.c. morphine, heroin and methadone initially increased before returning to control values. Similarly, both morphine and etorphine ED50 values, after i.c.v. administration, initially increased after pellet removal. Because this second manifestation of tolerance occurred during the rapid disappearance of the tolerance-induction drug, it was called withdrawal tolerance. The third manifestation of tolerance, seen after 3 days of pellet implantation, was characterized by the animal's return to a normal nociceptive sensitivity (control tail-flick latency) in the continued presence of the narcotic pellet. Because this adjustment involved an adaptation by the mice to high brain concentrations of narcotic, this third manifestation of tolerance was designated as a physiologic or homeostatic tolerance. The lability of this new homeostatic state (physiologic tolerance) may be associated with an altered sensitivity to naloxone as evidenced by naloxone-induced jumping (precipitated withdrawal).

Animals↗
PubMed1982

Cross tolerance to etorphine in rats tolerant to morphine-induced antidiuresis.

Previously in the analgesic tail flick assay, mice and rats implanted with morphine pellets were shown to be highly tolerant to subcutaneously administered morphine but not to etorphine. The present purpose was to see whether the same differential response would be found to the antidiuretic response of morphine and etorphine in water-loaded rats because the presence of such a differential response would be value in studying mechanisms of tolerance. Etorphine injected subcutaneously was about 1000x more potent than morphine in producing an antidiuretic response. Following chronic administration of morphine by pellet implantation, where the pellets remained in place during the drug challenge, profound tolerance developed to the antidiuretic effect of both morphine and etorphine. The dose-response curves for both were shifted to the right in non-parallel fashion with decreased slopes and antidiuretic efficacies. The large degree of tolerance developed to the antidiuretic effect of etorphine in morphine pellet implanted rats in contrast to the lack of development of tolerance to etorphine in the tail flick assay indicated that different mechanisms of development of tolerance exist for the two responses.

Animals↗
PubMed1982

Trans-stilbene oxide administration increased hepatic glucuronidation of morphine but decreased biliary excretion of morphine glucuronide in rats.

The effect of the inducing agent trans-stilbene oxide (TSO) on the metabolism and biliary excretion of [14C]morphine was studied in the isolated in situ perfused rat liver. After administration of morphine by intraportal injection or by the segmented retrograde intrabiliary injection technique, the TSO-treated group showed a marked decrease in the biliary recovery of morphine as its glucuronide conjugate [morphine-3-glucuronide (MG)]. However, recovery of MG in the venous outflow of the single pass perfusate was greatly increased. These findings suggested that TSO treatment enhanced the formation of MG from morphine and changed the primary route of hepatic elimination of MG. TSO treatment also decreased the excretion of morphine (as MG) in the bile of anesthetized renal-ligated rats. This decreased biliary function required several days to develop and appeared closely associated with the inductive effect of TSO. After i.v. administration of [14C]MG itself, biliary recovery was also markedly decreased in TSO-treated rats. It is postulated that the effect of the TSO treatment led to either a decrease in canalicular transport of MG into bile or an increase in the efficiency of transfer of MG to the blood at the sinusoidal side of the hepatocyte. Regardless of the mechanism, the results indicate the need to study compartmentalization of drug transport and metabolism functions.

Animals↗