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J M Fujimoto

Publications and source records attributed to J M Fujimoto.

At least 55 records · Page 3Linked to original sources
PubMed1990

Clonidine, administered intracerebroventricularly in mice, produces an anti-analgesic effect which may be mediated spinally by dynorphin A (1-17).

Clonidine, administered intracerebroventricularly, was shown to have two actions in the tail-flick test in mice: an overt anti-analgesic and a latent analgesic effect. The anti-analgesic effect was demonstrated by antagonism of the antinociceptive response to morphine, administered intrathecally. This anti-analgesic effect was attenuated by naloxone and nor-binaltorphimine, given intrathecally. Given intracerebroventricularly by itself, clonidine had no antinociceptive effect; however, the administration of naloxone and nor-binaltorphimine intrathecally uncovered the latent antinociceptive action of clonidine given intracerebroventricularly. This sensitivity to the opioid antagonists, given intrathecally, indicated that an endogenous anti-analgesic opioid might mediate the actions of clonidine at the spinal level. The putative opioid was postulated to be dynorphin A (1-17). Analgesia induced by intrathecally administered morphine was attenuated by the intrathecal administration of dynorphin A (1-17) at doses of less than 10 pg (5 fmol). This action of dynorphin was blocked by naloxone (5 fg, 0.014 fmol) and nor-binaltorphimine (10 ng, 12.3 pmol) at doses which did not block mu and kappa receptors in the spinal cord. The authors propose that clonidine, given intracerebroventricularly, activates an anti-analgesic system which descends spinally and is mediated by dynorphin A (1-17) in the spinal cord. This anti-analgesic effect of dynorphin A (1-17) appears to be a new function for dynorphin A (1-17).

Analgesics↗
PubMed1990

Systemic single dose morphine pretreatment desensitizes mice to the spinal antianalgesic action of dynorphin A (1-17).

The antianalgesic effect of dynorphin A (1-17) (dyn A) was demonstrated by i.c.v. administration of agonists (morphine, Tyr-D-Ala2-Gly-N-MePhe4-Gly-ol5, D-Pen2-D-Pen5-enkephalin, beta-endorphin, U50,488H and physostigmine) at 10 min and intrathecal administration of dyn A at 5 min before the tail-flick test in mice. This antianalgesic effect of dyn A was eliminated by 3 or 5.5 hr pretreatment s.c. with 10 or 100 mg/kg of morphine, respectively. This desensitization lasted for about 18 hr. Three-hour pretreatment intrathecally with dyn A also desensitized the mice to dyn A. Previously we had shown that i.c.v. administration of morphine simultaneously activates analgesic and antianalgesic systems and the latter is mediated spinally by dyn A, an endogenous antianalgesic opioid. Present results are consistent with that concept and systemic pretreatment with morphine may release dyn A in the spinal cord to produce the desensitization to the subsequently elicited antianalgesic action of dyn A.

Analgesia↗
PubMed1990

Brainstem sites differentially sensitive to beta-endorphin and morphine for analgesia and release of met-enkephalin in anesthetized rats.

Mapping of the brainstem regions sensitive to beta-endorphin and morphine for antinociception and Met-enkephalin release was performed in rats. Antinociception was assessed by the tail-flick test in pentobarbital-anesthetized rats and the release of immunoreactive Met-enkephalin from the spinal cord was measured by lumbar-cisternal perfusion in urethane-anesthetized rats. The sites in the brainstem most sensitive to beta-endorphin (2 micrograms) for inhibition of the tail-flick response and Met-enkephalin release were located in areas in the caudal medial medulla such as raphe obsacurus nucleus and raphe pallidus nucleus and the adjacent midline reticular formation. Sites in the rostral medial medulla were less sensitive to beta-endorphin for both antinociception and release of Met-enkephalin. The regions 1 mm and more lateral to the midline were not sensitive to beta-endorphin. The sites sensitive to morphine sulfate (4 micrograms) for antinociception were located in areas in the rostral ventromedial medulla such as raphe magnus nucleus, gigantocellular reticular nucleus and gigantocellular reticular nucleus alpha. Raphe obscurus nucleus, which was sensitive to beta-endorphin, was not sensitive to morphine for antinociception. Locus coeruleus was sensitive to morphine and beta-endorphin for antinociception. No sites sensitive to morphine were found for Met-enkephalin release. The correlation between the brainstem sites sensitive to beta-endorphin for the production of antinociception and the release of Met-enkephalin suggests that the antinociception induced by beta-endorphin is mediated by the release of Met-enkephalin. The findings of different brainstem sites sensitive to beta-endorphin and morphine support the hypothesis of different modes of pharmacological actions for beta-endorphin and morphine.

Analgesia↗
PubMed1989

Differential mechanisms mediating beta-endorphin- and morphine-induced analgesia in mice.

Effects of yohimbine, methysergide and naloxone given intrathecally (i.t.) and naloxone given intracerebroventricularly (i.c.v.) on inhibition of the tail-flick and hot-plate response induced by beta-endorphin and morphine given i.c.v. were studied in male ICR mice. Yohimbine (1.5 and 15 micrograms) and methysergide (1.5 and 15 micrograms) injected i.t. antagonized inhibition of the tail-flick response induced by morphine but not beta-endorphin administered i.c.v. On the other hand, naloxone (20 ng) injected i.t. antagonized inhibition of the tail-flick response induced by i.c.v. administered beta-endorphin but not morphine. Yohimbine and methysergide given i.t. did not antagonize inhibition of the hot-plate response induced by morphine nor did naloxone given i.t. antagonized i.c.v. beta-endorphin-induced inhibition of the hot-plate response. Naloxone given i.c.v. was more effective in antagonizing morphine-induced inhibition of the tail-flick and hot-plate response than inhibition induced by beta-endorphin given i.c.v. Naloxone at doses (0.1 and 1 microgram) which effectively reversed inhibition of the tail-flick response to i.c.v. morphine was not effective in reversing the i.c.v. beta-endorphin-induced inhibition of the tail-flick response. Our results indicate that beta-endorphin and morphine produce analgesia by stimulating separate types of opioid receptors, epsilon- for for beta-endorphin and mu- for morphine, and activate separate descending pain modulatory control systems. The supraspinal epsilon system stimulated by beta-endorphin is mediated by activation of spinal opioid receptors whereas the supraspinal mu system stimulated by morphine is mediated by activation of spinal alpha 2-adrenoceptors and serotonin receptors for the production of analgesia.

Analgesia↗
PubMed1989

Multiplicative interaction between intrathecally and intracerebroventricularly administered mu opioid agonists but limited interactions between delta and kappa agonists for antinociception in mice.

Simultaneous action of morphine on supraspinal and spinal sites produces a multiplicative interaction for antinociception which may be important for the analgesia produced by systemically administered morphine. The purpose of this study was to see whether other agonists with more receptor selective opioid actions than morphine would also produce this multiplicative interaction. DAMPGO (Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5), DPDPE (D-Pen2, D-Pen5, enkephalin) and U50-488H, opioid agonists highly selective for mu, delta and kappa receptors, respectively, were administered alone i.c.v. or intrathecally (i.t.) or in combination (i.c.v. plus i.t.) to determine ED50 values for the tail-flick response in mice. These ED50 values were examined isobolographically in relation to the theoretical additive ED50 values by the potency ratio method. First, DAMPGO given i.cv and i.t. was similar to morphine, indicating that simultaneous supraspinal and spinal mu agonist administration produce the multiplicative interaction. Second, concurrent administration of DPDPE or U50,488H, i.c.v. and i.t., as well as cross-over combinations of DPDPE at one and U50,488H at the other site, produced additive interactions only. The multiplicative interaction was a property characteristic of mu but not delta and kappa agonists. Based on the similarity between morphine and DAMPGO, it was postulated that both mu agonists act on redundant descending pain inhibitory pathways to produce multiplication. A second mechanism for multiplicative interaction was based on the difference between DAMPGO and morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Intracerebroventricular physostigmine-induced analgesia: enhancement by naloxone, beta-funaltrexamine and nor-binaltorphimine and antagonism by dynorphin A (1-17).

The antinociceptive action (tail-flick test) of physostigmine given i.c.v. to mice was enhanced by the administration intrathecally (i.t.) of narcotic antagonists. Doses, i.t., as low as 0.1 fentog of naloxone, 0.25 ng of beta-funaltrexamine and 0.1 ng of nor-binaltorphimine enhanced physostigmine, 2 micrograms i.c.v., analgesia. These doses of opioid antagonists did not inhibit spinal mu receptors or kappa receptor agonist-induced analgesia as assessed by absence of effect on Tyr-D-Ala2-N-MePhe4-Gly-ol5 or U50,488H i.t. analgesia. Enhancing effects of the opioid antagonists were interpreted to indicate that i.c.v. physostigmine-induced analgesia was mediated spinally by an endogenous opioid which had an antagonistic effect. This putative opioid antagonist was postulated to be dynorphin A (1-17). Thus, i.t. administration of small doses of less than 10 pg of dynorphin was shown to antagonize the analgesic action of physostigmine, i.c.v. Furthermore, this effect of dynorphin was attenuated by the doses of naloxone, beta-funaltrexamine or nor-binaltorphimine which were effective in enhancing physostigmine-induced analgesia. We concluded that physostigmine given i.c.v. had two actions, the first produced analgesia and the second activated a system which had an antianalgesic effect. Evidence indicated that the latter effect was mediated by dynorphin A (1-17). This concept of dynorphin action may be the basis for some of the unusual findings of the analgesic action of naloxone in other situations and support the concept for a descending dynorphin A (1-17)-mediated antianalgesic system.

Analgesia↗
PubMed1988

Comparisons of descending pain inhibitory pathways activated by beta-endorphin and morphine as characterized by supraspinal and spinal antinociceptive interactions in mice.

Morphine administered concurrently by i.c.v. plus intrathecal (i.t.) injection produces a multiplicative (synergistic) interaction for antinociception in the tail-flick test. Inasmuch as i.c.v. administered beta-endorphin has been proposed to produce antinociception by activating a descending pain inhibitory system different from that activated by morphine, the present experiments compared the two systems in mice. The responses to i.c.v., i.t. and combinations of i.c.v. plus i.t. administration of morphine and beta-endorphin were evaluated by determination of ED50 values which were plotted as isobolograms and compared to calculated theoretical additive ED50 values. The following combinations gave additive interactions: i.c.v. plus i.t. beta-endorphin, i.c.v. beta-endorphin plus i.t. morphine and i.t. morphine plus i.t. beta-endorphin. These results were consistent with the hypothesis that i.c.v. beta-endorphin stimulates supraspinal epsilon receptors which activate a descending pathway involving enkephalinergic neuronal mediation and spinal postsynaptic mu receptors. Stimulation of these mu receptors by i.t. morphine or i.t. beta-endorphin together with the supraspinal effect of beta-endorphin resulted in an additive interaction. Multiplicative interactions were obtained for the following combinations: i.c.v. morphine plus i.t. morphine, i.c.v. morphine plus i.t. beta-endorphin and i.c.v. morphine plus i.c.v. beta-endorphin. Morphine administered i.c.v. stimulated supraspinal mu receptors to activate a descending pain inhibitory pathway which is mediated spinally by monoamines. The i.t. agonists in this case activated the spinal mu receptor which is presumed to be part of the beta-endorphin descending pathway described above. Thus, when both pathways were activated simultaneously the interaction was multiplicative.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1988

Morphine antinociception in different strains of mice: relationship of supraspinal-spinal multiplicative interaction to tolerance.

In the rat and mouse when morphine is coadministered intracerebroventricularly (i.c.v.) in the brain and intrathecally (i.t.) in the spinal cord, a multiplicative (synergistic) interaction occurs for the antinociceptive response. In the male Swiss Cox mouse, with the development of a high degree of systemic tolerance to morphine, this multiplicative interaction decreases (becomes additive), whereas no change occurs in the ED50 for the i.c.v. or i.t. site itself. The purpose of the present study was to extend these findings in one mouse strain to other strains in order to determine how generally applicable such findings are to the phenomenon of tolerance to morphine. Eight different strains of outbred mice were used in the antinociceptive tail-flick test to quantify the multiplicative interaction of simultaneous administration (i.c.v. and i.t.) in relation to the amount of tolerance developed to morphine administered systemically (s.c.). Even though the control ED50 values for s.c. morphine were similar among strains, the amounts of tolerance developed by 3 days of implantation of a morphine pellet were very different (2-18-fold). A relationship was found between the degree of tolerance developed to s.c. morphine and changes in the multiplicative interaction (as reflected by changes in the i.c.v. plus i.t. morphine ED50 values). In control animals, a multiplicative i.c.v.-i.t. interaction was produced in six of the eight strains, whereas an additive interaction was shown in the remaining two strains. With 3 days of morphine pellet implantation, in three strains which developed a large amount of tolerance to s.c. morphine (7-18-fold), the multiplicative interaction decreased to an additive interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Development of tolerance to respiratory depression in morphine- and etorphine-pellet-implanted mice.

Tolerance to opiate-induced depression of respiratory rate was studied in unanesthetized mice following chronic treatment with morphine or etorphine. Mice implanted subcutaneously (s.c.) with morphine pellets showed development of tolerance to morphine administered both s.c. and intracerebroventricularly (i.c.v.) and to s.c. etorphine and heroin. However, no cross-tolerance to i.c.v. etorphine or heroin was observed. In contrast, mice implanted with etorphine pellets demonstrated development of tolerance to all 3 agents given either s.c. or i.c.v. These findings on development of tolerance to opiate-induced respiratory depression differ from our previous studies measuring analgesia in which mice tolerant to s.c. morphine did not demonstrate development of tolerance to s.c. etorphine or heroin (unidirectional non-cross-tolerance). To investigate a possible mechanism for this difference in development of tolerance, apparent pA2 values for respiratory rate depression were determined for s.c. morphine-naloxone and etorphine-naloxone. The apparent pA2 values for these two opiates were similar, in contrast to the dissimilar apparent pA2 values previously found when analgesia was measured. The apparent pA2 values demonstrated differences between the respiratory depressant and analgesic effects of these opiates, but there was no obvious relationship between apparent pA2 values and the absence of unidirectional non-cross-tolerance observed for respiratory depression.

Animals↗
PubMed1987

Increased permeability of the rat biliary tree by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment and protection by hepatoactive agents.

Male Sprague-Dawley rats were treated ip on Day 0 with 0, 20, 50, or 100 micrograms/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and biliary tree permeability was evaluated on Days 2, 4, 7, 10, 14, or 20 by segmented retrograde intrabiliary injection of [3H]sucrose or [14C]mannitol. Seven days after 100 micrograms/kg TCDD, the percentage recovery in bile of both [3H]sucrose (73.9 +/- 4.2 vs 27.6 +/- 7.6, control vs TCDD, means +/- SE) and [14C]mannitol (22.7 +/- 2.2 vs 12.1 +/- 2.2) was decreased, demonstrating that the permeabilities of both the intracellular (canalicular) and paracellular pathways were increased. Seven days after 50 micrograms/kg TCDD, the recovery of [3H]sucrose was decreased (73.5 +/- 5.4 vs 39.0 +/- 2.8) but the recovery of [14C]mannitol was not (25.5 +/- 1.5 vs 22.9 +/- 1.9). Thus, an increase in paracellular permeability is obtained at a lower dose of TCDD. In rats treated with 100 micrograms/kg TCDD on Day 0, co-treatment with chlordecone (15 mg/kg/day on Days 2-6) or thyroxine (50 micrograms/kg on Day 2) had no effect. Pregnenolone-16 alpha-carbonitrile (75 mg/kg/day on Days 4-6) treatment increased [14C]mannitol recovery in both TCDD and control groups; its effect must not be specific. Methimazole given in drinking water (0.5%) on Days -7 through 7 reversed the increased permeability effects of TCDD (100 micrograms/kg) without affecting the biliary tree permeability ([14C]mannitol recovery) of control animals.

Animals↗
PubMed1987

Antagonism by nalmefene of systemic and intrathecal morphine-induced analgesia in mice.

Nalmefene is an orally active opiate antagonist structurally related to naloxone and naltrexone. In this study using two different strains of mice (Swiss Cox and ICR), the antagonist activity of nalmefene given subcutaneously (sc) was quantified by determination of the apparent pA2 values against the antinociceptive activity (tail flick and hot plate tests) of morphine given sc or intrathecally (lumbar spinal cord). The apparent pA2 values (constrained to a slope of -1) were 8.06 (7.79-8.33) in Swiss Cox mice and 7.81 (7.62-8.00) in ICR mice in the tail flick test with sc morphine. These values were larger than the corresponding value for naloxone in ICR mice, 7.35 (7.10-7.60). The hot plate test provided similar results: the apparent pA2 values for nalmefene with sc morphine were 8.14 (7.89-8.39) in Swiss Cox mice and 7.81 (7.65-7.97) in ICR mice, values which were different from naloxone 7.33 (7.23-7.42) in ICR mice. Apparent pA2 values for nalmefene with intrathecal morphine were not different from those for naloxone in the tail flick test. Thus, these sets of results suggest that it may be worthwhile to further determine whether systemic nalmefene might possibly possess an advantage over naloxone in antagonizing systemic side effects of morphine arising from local spinal morphine administration.

Analgesia↗
PubMed1986

Demonstration of cell sidedness in hepatic transfer of morphine and morphine glucuronide in the rat.

The purpose of this study was to demonstrate hepatic cell sidedness for the transfer of [14C]morphine and [14C]morphine glucuronide. A tracer dose of [14C]morphine was administered by segmented retrograde intrabiliary injection into the bile duct cannula of the urethane-anesthetized rat or the in situ isolated perfused liver preparation. The bile from the first, and the single pass perfusate from the second preparation, respectively, were analyzed for the radioactive components. Various doses of morphine were given intraportally in these preparations 5 min before the [14C]morphine to influence the recovery of the radioactive components. As the dose of morphine increased, the recovery in bile of [14C]morphine glucuronide decreased while [14C]morphine remained unchanged. In the perfusate, the morphine loading increased the recovery of [14C]morphine, but the [14C]morphine glucuronide content was unchanged. These sets of results indicated that morphine loading inhibited the formation of morphine glucuronide by isotope dilution, which should have led to an increase in [14C]morphine in the cell. Because of the presence of cell sidedness, the increased intracellular [14C]morphine was directed toward the perfusate and not toward the bile. The decrease in [14C]morphine glucuronide synthesis was manifested by a decrease in its excretion into bile, but not into perfusate. Further demonstration of cell sidedness was obtained by manipulation of these systems by chlordecone and trans-stilbene oxide pretreatment of the rats. The directionality of flow of [14C]morphine and [14C]morphine glucuronide out of the liver emanates from liver cell sidedness.

Animals↗
PubMed1986

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on IgA serum and bile levels in rats.

Serum IgA is actively transported from blood to bile against a concentration gradient in the liver by the binding of dimeric IgA to secretory component, endocytosis and transport to the bile canaliculus by vesicles. As 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to elicit hepatotoxicity, the effects of TCDD on rat serum and bile IgA levels were investigated. Rats were orally administered 50 micrograms TCDD/kg body weight in 95% corn oil: 5% acetone. At days 5, 10, 15, 20 and 30 after treatment, rats were anesthetized and a cannula inserted into the bile duct for collection of bile. In addition, blood was drawn, and, after euthanasia, the liver and thymus weights were recorded. Enzyme-linked immunosorbent assay (ELISA) techniques were employed to determine IgA in serum and bile and IgG levels in serum. Rocket immunoelectrophoresis was carried out to support ELISA results. It was found that serum IgA increased with time while serum IgG remained unchanged. In addition, while serum IgA levels were increasing, there was a concomitant decrease in biliary IgA. Thymus and liver weight changes were also observed. The data indicate that TCDD affects hepatic clearance of serum dimeric IgA and suggests that liver damage may be reflected by increased serum levels of IgA.

Animals↗
PubMed1986

Release of immunoreactive met-enkephalin by intraventricular beta-endorphin in anesthetized rats.

The release of immunoreactive met-enkephalin and leu-enkephalin from the spinal cord by intraventricular injection of different doses of beta-endorphin was studied using the intrathecal perfusion technique. The intraventricular beta-endorphin elicited the release of immunoreactive met-enkephalin from the spinal cord in a dose dependent manner. Immunoreactive leu-enkephalin in the spinal perfusate was not increased after intraventricular beta-endorphin injection. Both immunoreactive met-enkephalin and leu-enkephalin in the spinal cord were not changed by low doses (2-6 micrograms) of beta-endorphin but were increased markedly by 60-70% after high doses of beta-endorphin (32-64 micrograms). It is likely that the biosynthesis of enkephalins was also increased after intraventricular beta-endorphin injection. Intraventricular naloxone, 30 micrograms did not induce any release of immunoreactive met-enkephalin from the spinal cord and did not block the release of immunoreactive met-enkephalin induced by intraventricular beta-endorphin, 15 micrograms.

Animals↗
PubMed1986

Comparison of the inhibition of biliary excretion produced by certain inducing agents including 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Rats were treated with chlordecone, mirex, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and respective solvent vehicle. Under urethane or pentobarbital anesthesia, the bile duct was cannulated and radioactive morphine, imipramine, or ouabain was given by segmented retrograde intrabiliary injection. The spectrum of inhibition of biliary excretion by chlordecone and mirex were similar in that morphine glucuronide and in part polar imipramine metabolite recoveries in bile were decreased; ouabain recovery was unaffected. TCDD was different in that it markedly decreased the recovery of ouabain. Thus, it appears that chlordecone, mirex, and TCDD inhibit the canalicular transport of the glucuronide metabolites of morphine and imipramine into bile, and TCDD affects in addition the canalicular transport of ouabain into bile.

Animals↗
PubMed1986

Spinal release of immunoreactive Met-enkephalin by intraventricular beta-endorphin and its analogs in anesthetized rats.

We have reported previously that i.v.t. beta-endorphin increases the release of immunoreactive Met-enkephalin but not Leuenkephalin or dynorphins from the spinal cord. To determine if the effect is specific to beta-endorphin, the present investigation tested i.v.t. beta-endorphin, its analogs and other opiate agonists with different opioid receptor activities for their ability to release Met-enkephalin using an intrathecal perfusion technique. Human beta-endorphin and its analogs, human beta-endorphin-(1-30), -(1-29) and -(1-28) which have an identical amino acid sequence in the NH2-terminus showed reduced stepwise potencies in releasing Met-enkephalin. The results correlated well with their analgesic potencies. Des-Met5-camel beta-endorphin (64 micrograms i.v.t.) which does not have a complete sequence of Met-enkephalin in its NH2-terminus but still retains 20% of camel beta-endorphin analgesic potency caused the spinal release of Met-enkephalin. Morphine (mu opioid receptor agonist, 40 micrograms), D-Ala2-D-Leu5-enkephalin (delta opioid receptor agonist, 80 micrograms) and U-50488H (kappa opioid receptor agonist, 160 micrograms) injected i.v.t. were unable to cause any release of Met-enkephalin. High-performance liquid chromatography after Sephadex G-50 gel chromatography indicated that the immunoreactive Met-enkephalin in the spinal perfusate released by i.v.t. beta-endorphin had a retention time identical to authentic Met-enkephalin. Intraventricular injection of Met-enkephalin, 4 nmol (2.3 micrograms), caused little increase of Met-enkephalin immunoreactivity in the spinal perfusate, whereas 4 nmol of i.v.t. beta-endorphin caused a marked increase of Met-enkephalin in the spinal perfusate. Inhibition of peptidase by i.v.t. aprotinin and bacitracin does not prevent the spinal release of Met-enkephalin induced by i.v.t. beta-endorphin. It is concluded that the release of Met-enkephalin was specific to beta-endorphin and the results were not due to cross-immunoreactivity of beta-endorphin or its metabolites.

Amino Acid Sequence↗
PubMed1986

Microwave facilitation of methylatropine antagonism of central cholinomimetic drug effects.

Pilocarpine-induced hypothermia and oxotremorine-induced tremors in mice are central cholinomimetic drug effects that are readily blocked by the muscarinic antagonist atropine. However, the quaternary ammonium derivative of atropine, methylatropine, is unable to block these cholinomimetic drug effects by virture of its inability to penetrate the blood-brain barrier (BBB) and blood-cerebral spinal fluid barrier (B-CSFB). Dose-response curves for pilocarpine and oxotremorine effects are not appreciably affected either by pretreatment with methylatropine (1.0 mg/kg) or by exposure to moderate-level microwave irradiation (2.45 GHz, 23.7 W/kg, CW, 10-min exposure). However, in mice receiving both the methylatropine pretreatment and microwave irradiation, the dose-response curves for both pilocarpine and oxotremorine effects were significantly shifted to the right, signifying a central anticholinergic action by methylatropine. These data indicate that a single acute exposure to a thermogenic level of microwave irradiation facilitates methylatropine antagonism of centrally mediated cholinomimetic drug effects. One possible explanation for this observation is that microwave radiation may enhance passage of quaternary ammonium compounds like methylatropine across the BBB and B-CSFB.

Animals↗