Biomedical subjects

L F Tseng

Publications and source records attributed to L F Tseng.

At least 109 records · Page 6Linked to original sources

PubMed1991

Dynorphins other than dynorphin A(1-17) lack spinal antianalgesic activity but do act on dynorphin A(1-17) receptors.

In recent publications we have proposed that dynorphin (Dyn) A(1-17) functions as an antianalgesic modulator to oppose opioid-induced antinociception in mice. In the present experiments using the tail-flick response in mice, other Dyns [Dyn A(1-8), Dyn A(1-13), Dyn A(2-17), Dyn B and alpha- and beta-neoendorphin] when administered intrathecally (i.t.) were shown not to have antianalgesic activity even at high doses (0.5-1 pmol). These Dyns, i.t., did not antagonize the antinociception produced by physostigmine administered i.c.v. or morphine given i.t. These Dyns lacked the intrinsic antianalgesic activity of Dyn A(1-17). However, they had affinity for Dyn A(1-17) receptors as shown in several ways. 1) The antagonism of physostigmine antinociception produced by Dyn A(1-17) given i.t. was reversed by these Dyns given together with Dyn A(1-17). 2) The effect of endogenously released Dyn A(1-17) was reversed. Administered i.c.v., clonidine simultaneously activates antinociceptive and antianalgesic systems [latter mediated spinally by Dyn A(1-17) release]. Thus, these Dyns given i.t. inhibited the action of endogenously released Dyn A(1-17) and allowed the full manifestation of the antinociceptive action of clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Different mechanisms mediating tail-flick inhibition induced by beta-endorphin, DAMGO and morphine from ROb and GiA in anesthetized rats.

The effects of beta-endorphin, D-Ala2-NMePhe4-Gly-ol-enkephalin (DAMGO) and morphine microinjected into raphe obscurus nucleus (ROb) and gigantocellular reticular nucleus alpha (GiA) in inhibiting the tail-flick response were studied in pentobarbital anesthetized rats. beta-Endorphin (0.1-3 micrograms) microinjected into ROb inhibited the tail-flick response dose-dependently and produced 100% inhibition at high doses (greater than 3 micrograms). DAMGO [0.004-0.015 micrograms] injected into ROb, also dose-dependently, inhibited the tail-flick response but reached a plateau of 60 to 80% inhibition at high doses (greater than 0.015 micrograms). Morphine (10-60 micrograms) injected into ROb produced only a small inhibition (less than 20% inhibition) even at high doses (greater than 60 micrograms). The rank order of potency of these opioids on the tail-flick inhibition was DAMGO greater than beta-endorphin greater than morphine. Morphine (1-10 micrograms) and DAMGO (0.004-0.03 micrograms) microinjected into GiA produced dose-dependent inhibitions of the tail-flick response and high doses of these two mu agonists fully inhibited the tail-flick response. However, beta-endorphin (0.1-10 micrograms) injected into GiA produced a small but dose-dependent inhibition of the tail-flick response (less than 60% inhibition). The rank order of potency of these opioids on the tail-flick inhibition was DAMGO greater than beta-endorphin greater than morphine. The inhibition of the tail-flick response induced by beta-endorphin (2 micrograms) microinjected into ROb was blocked by the coadministration of beta-endorphin-[1-27] (6 micrograms), but not naloxone (1 microgram).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1990

Differential effects of sulfated cholecystokinin octapeptide and proglumide injected intrathecally on antinociception induced by beta-endorphin and morphine administered intracerebroventricularly in mice.

The effects of sulfated cholecystokinin octapeptide (CCK-8s) and CCK-8s antagonist, proglumide, given intrathecally (i.t.) on inhibition of the tail-flick and hot-plate paw-licking responses induced by beta-endorphin and morphine given intracerebroventricularly (i.c.v.) were studied in male ICR mice. Both CCK-8s (up to 0.5 ng) and proglumide (up to 10 micrograms) injected alone did not affect significantly the control latencies of the tail-flick and paw-licking responses. I.t. injection of CCK-8s as doses from 0.125 to 0.5 ng dose dependently attenuated inhibition of the tail-flick response induced by i.c.v. administered beta-endorphin. The antagonistic effect of CCK-8s on beta-endorphin-induced inhibition was blocked by the co-i.t. injection of proglumide (0.1-1 micrograms) in a dose-dependent manner. High doses (2.5-10 micrograms) of proglumide given i.t. dose dependently enhanced inhibition of the tail-flick response induced by i.c.v. administered beta-endorphin. However, i.t. injection of CCK-8s and proglumide did not affect inhibition of the paw-licking response induced by i.c.v. administered beta-endorphin. The inhibitions of the tail-flick and paw-licking responses induced by i.c.v. administered morphine were not affected by i.t. injection of CCK-8s or proglumide. Our results suggest that CCK-8s in the spinal cord may play an important modulatory role in attenuating the descending pain inhibition induced by i.c.v. administered beta-endorphin but not morphine.

Analgesics↗

PubMed1990

Different types of opioid receptors mediating analgesia induced by morphine, DAMGO, DPDPE, DADLE and beta-endorphin in mice.

The effects of intracerebroventricular (i.c.v.) administration of D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2 (CTOP), a selective mu-opioid receptor antagonist, (Allyl)2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174864) and (N,N-Bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH (ICI 154129), selective delta-opioid receptor antagonists on blocking analgesia induced by beta-endorphin, morphine, D-Ala2-NMePhe4-Gly-ol-enkephalin (DAMGO), D-Ala2-D-Leu5-enkephalin (DADLE) and D-Pen2-enkephalin (DPDPE) administered i.c.v. were studied in male ICR mice. The analgesia was assessed by the tail-flick and paw-licking (hot-plate) tests. The potencies of opioid agonists injected i.c.v. for producing analgesia were DAMGO greater than DADLE greater than beta-endorphin greater than morphine greater than DPDPE. Intracerebroventricular administration of CTOP (0.05 micrograms) selectively antagonized inhibition of the tail-flick and paw-licking response induced by morphine, DAMGO or DADLE but not beta-endorphin or DPDPE. ICI 174864 (5 micrograms) and ICI 154129 (5 micrograms) injected i.c.v. selectively antagonized analgesia induced by DPDPE or DADLE but not beta-endorphin, morphine or DAMGO injected i.c.v. These results indicate that analgesia induced by morphine and DAMGO is mediated by the stimulation of mu-opioid receptors while analgesia induced by DPDPE is mediated by the stimulation of delta-opioid receptors. DADLE-induced analgesia is mediated by the stimulation of both mu- and delta-opioid receptors. Analgesia induced by beta-endorphin is mediated by neither mu- nor delta-opioid receptors.

Analgesia↗

PubMed1990

Lack of antinociceptive cross-tolerance between intracerebroventricularly administered beta-endorphin and morphine or DPDPE in mice.

Antinociceptive tolerance and cross-tolerance to intracerebroventricular (i.c.v.) beta-endorphin, morphine, and DPDPE (D-Pen2-D-Pen5-enkephalin) induced by a prior i.c.v. administration of beta-endorphin, morphine and DPDPE, respectively, were studied in mice. Acute tolerance was induced by i.c.v. pretreatment with beta-endorphin (0.58 nmol), morphine (6 nmol) and DPDPE (31 nmol) for 120, 180 and 75 min, respectively. Various doses of beta-endorphin, morphine or DPDPE were then injected. The tail-flick and hot-plate tests were used as antinociceptive tests. Pretreatment of mice with beta-endorphin i.c.v. reduced inhibition of the tail-flick and hot-plate responses to i.c.v. administered beta-endorphin, but not morphine and DPDPE. Pretreatment of mice with morphine i.c.v. reduced inhibition of the tail-flick and hot-plate responses to morphine but not beta-endorphin. Pretreatment of mice with DPDPE reduced inhibition of the tail-flick and hot-plate responses to DPDPE but not beta-endorphin. The results indicate that one injection of beta-endorphin, morphine or DPDPE induces acute antinociceptive tolerance to its own distinctive opioid receptor and does not induce cross-tolerance to other opioid agonists with different opioid receptor specificities. The data support the hypothesis that beta-endorphin, morphine and DPDPE produce antinociception by stimulating specific epsilon, mu- and delta-opioid receptors, respectively.

Analgesics↗

PubMed1990

Spinal dynorphin A (1-17): possible mediator of antianalgesic action.

Earlier studies from this laboratory indicated that intracerebroventricular administration of physostigmine and clonidine activated both a spinal descending analgesic and antianalgesic system. It was proposed that the latter was mediated spinally by dynorphin A (1-17), because small intrathecal doses (fmol) of dynorphin A (1-17) antagonized analgesia, while intrathecal administration of naloxone and nor-binaltorphimine (at doses which had no effect on spinal mu and kappa receptors) enhanced analgesia by attenuating the antianalgesic component. In the present studies in mice, using the tail-flick response, intrathecal administration of dynorphin antibody (antiserum to dynorphin) enhanced the analgesic effect of (10 min) physostigmine and clonidine given intraventricularly. Peak effect for the antiserum was at 1 hr. Inhibition of the tail-flick response, induced by DAMGO (Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, a mu agonist), U50, 488 H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate hydrate, a kappa agonist) and morphine was also enhanced by intrathecal administration of dynorphin antiserum. Thus, a variety of analgesic agonists appear to activate a dynorphin-mediated antianalgesic system. Such a system appears not to be activated by intraventricular administration of beta-endorphin and DPDPE (D-Pen2-D-Pen5-enkephalin, a delta agonist) because neither beta-endorphin- nor DPDPE-induced analgesia was enhanced by intrathecal administration of antiserum. The results of the experiments with the antibody provide further evidence to support the role of dynorphin A (1-17), as a putative endogenous opioid, which mediates an antianalgesic descending system in the spinal cord.

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

PubMed1990

Tolerance to delta- but not mu-opioid receptors in the spinal cord attenuates inhibition of the tail-flick response induced by beta-endorphin administered intracerebroventricularly in mice.

Male ICR mice were rendered tolerant by intrathecal (IT) injection once a day with either mu-agonist, D-Ala2-NMePhe4-Gly-ol-enkephalin (DAMGO) or delta-agonist, D-Pen2-D-Pen5-enkephalin (DPDPE) (toleragen) by doubling the dose each day starting from 0.125 and 1 microgram for DAMGO and DPDPE, respectively, for 6 days. On day 6, the magnitude of tolerance was assessed by establishing IT dose-response lines for the effect of the chronic drug given as bolus injections (probe). The antinociception was assessed by the tail-flick and hot-plate test. Repeated IT injections of DPDPE reduced inhibition of the tail-flick and hot-plate response induced by DPDPE (ED50 values for DPDPE increase 10-fold) but not DAMGO. Repeated IT injections of DAMGO reduced inhibition of the tail-flick and hot-plate response induced by DAMGO (ED50 value for DAMGO increase 7- to 10-fold) but not DPDPE. The effects of the tolerance to mu- and delta-opioid receptor activity in the spinal cord on inhibition of the tail-flick and hot-plate response induced by intracerebroventricularly (ICV) administered beta-endorphin and morphine were then studied. beta-Endorphin or morphine at different doses were injected ICV 4 hr after the last IT injection of DPDPE or DAMGO. Repeated IT bolus injections of DPDPE reduced inhibition of the tail-flick response but not the hot-plate response induced by beta-endorphin. On the other hand, repeated IT bolus injections of DAMGO did not affect inhibition of the tail-flick and hot-plate response induced by beta-endorphin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Different mechanisms mediate beta-endorphin- and morphine-induced inhibition of the tail-flick response in rats.

The studies were done to determine whether inhibition of the tail-flick response induced by beta-endorphin and morphine microinjected into periaqueductal central gray (CG) was mediated by stimulating different types of opioid receptors and by activating different descending pain modulatory systems in rats. beta-Endorphin (0.3-20 micrograms) or morphine (0.3-20 micrograms) microinjected bilaterally into CG produced a dose-dependent inhibition of the tail-flick response. Naloxone (0.3-3 micrograms) injected into CG was more effective in antagonizing inhibition of the tail-flick response induced by CG administered morphine than by beta-endorphin. beta-Endorphin-(1-27) (3 micrograms) injected CG effectively antagonized CG beta-endorphin-induced inhibition of the tail-flick response but slightly potentiated CG morphine-induced inhibition. Intrathecal injection of naloxone (0.3-30 micrograms) dose-dependently reversed inhibition of the tail-flick response induced by beta-endorphin (2 micrograms) but not by morphine (4 micrograms) injected into CG. On the other hand, yohimbine (0.3-30 micrograms) injected intrathecally dose-dependently antagonized inhibition of the tail-flick response induced by morphine (4 micrograms) but not by beta-endorphin (2 micrograms) given into CG. It was concluded that beta-endorphin and morphine produce inhibitions of the tail-flick response by stimulating epsilon and mu opioid receptors, respectively, and the descending pain modulatory system activated by beta-endorphin from CG involves spinal opioid receptors but not alpha-2 adrenoceptors whereas the descending system activated by morphine from CG involves spinal alpha-2 adrenoceptors but not opioid receptors.

Analgesia↗

PubMed1990

Delta but not mu-opioid receptors in the spinal cord are involved in antinociception induced by beta-endorphin given intracerebroventricularly in mice.

The present studies were designed to determine what type of opioid receptor, mu or delta, in the spinal cord was involved in beta-endorphin-induced antinociception. The tail-flick response was used as an antinociceptive test. Intrathecal (i.t.) injection of ICI-174,864 [(Allyl)2-Tyr-Aib-Aib-Phe-Leu-OH] (10 micrograms) or ICI-154,129 [(N,N-Bisallyl)-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH] (20 micrograms), delta-opioid receptor antagonists, but not beta-funaltrexamine (0.025 microgram), a mu-opioid receptor antagonist, antagonized inhibition of the tail-flick response induced by beta-endorphin given i.c.v. However, i.t. injection of the same dose of ICI-174,864, ICI-154,129 or beta-funaltrexamine did not affect inhibition of the tail-flick response induced by morphine given i.c.v. Mice were pretreated i.c.v. with either beta-endorphin (2 micrograms), morphine (2 micrograms) or saline (5 microliters) for 2, 3 or 4 hr (which were times that the tail-flick response was no longer inhibited) and were injected i.t. with various doses of D-Ala2-NMePhe4-Gly-ol-enkephalin (a selective mu-opioid receptor agonist), D-Ala2-D-Leu5-enkephalin (a mu- and delta-opioid receptor agonist) or D-Pen2-D-Pen5-enkephalin (a delta-opioid receptor agonists). The tail-flick response was performed 10 min after i.t. injection. A single i.c.v. pretreatment with beta-endorphin for 2 and 3 hr, but not 4 hr, reduced markedly the inhibition of the tail-flick response induced by D-Pen2-D-Pen5-enkephalin and D-Ala2-DLeu5-enkephalin, but not D-Ala2-NMePhe4-Gly-ol-enkephalin, injected i.t.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1988

Release of a dynorphin A (1-8) degrading enzyme from the spinal cord by intraventricular morphine in the rat.

Intraventricular injection of morphine sulfate, 40 micrograms, released an enzyme from the spinal cord into the perfusate which degraded dynorphin A (1-8) and, to a lesser extent, dynorphin A (1-13) in urethane anesthetized rats. The enzyme did not degrade dynorphin A (1-17), Met-enkephalin, Leu-enkephalin, substance P and neurotensin. This dynorphin A (1-8) degrading enzyme was inhibited by aprotinin, thiorphan, and, to a lesser extent, by bacitracin but was not inhibited by bestatin. A kinetic study of the interaction between dynorphin A (1-8) and aprotinin with the enzyme indicated that it is competitive in nature. The pharmacological significance of the findings is still unknown.

Animals↗

PubMed1988

Beta-endorphin-(1-27) antagonizes beta-endorphin- but not morphine-, D-Pen2-D-Pen5-enkephalin- and U50, 488H-induced analgesia in mice.

beta-Endorphin-(1-27), administered intraventricularly has been previously reported to block the analgesia induced by beta-endorphin injected intraventricularly. The present study was to determine if the blocking effect of beta-endorphin-(1-27) was specific to beta-endorphin which stimulates epsilon receptors, but not to other opioids with activity at different opioid receptors. The antagonistic effects of beta-endorphin-(1-27) on the analgesia induced by beta-endorphin (epsilon-opioid receptor agonist), D-Ala2-NMePhe4-Gly-ol-enkephalin(DAGO) and morphine, (mu-opioid receptor agonists), D-Pen2-D-Pen5-enkephalin(DPDPE) and D-Ala2-D-Leu5-enkephalin(DADLE) (delta-opioid receptor agonists) and U-50, 488H (kappa-opioid receptor agonist) were studied. beta-Endorphin-(1-27) injected intraventricularly, at doses which, when injected alone did not produce analgesia, antagonized the analgesia induced by beta-endorphin given intraventricularly. However, the analgesia induced by DAGO, morphine, DPDPE, DADLE and U-50, 488H given intraventricularly was not antagonized by beta-endorphin-(1-27). The data suggest that beta-endorphin-(1-27) selectively blocks the analgesia induced by the stimulation of epsilon receptors but not by the stimulation of mu, delta, and kappa receptors. The results support the previously proposed hypothesis that beta-endorphin produces its analgesia by stimulating specific epsilon receptors.

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

PubMed1988

Intrathecal beta-funaltrexamine antagonizes intracerebroventricular beta-endorphin- but not morphine-induced analgesia in mice.

We have reported previously that beta-endorphin and morphine administered supraspinally produce analgesia by activating different descending pain inhibitory systems in rats. The descending system activated by beta-endorphin involves a spinal endorphinergic system whereas the descending system activated by morphine does not. To determine if this differential action of intraventricular beta-endorphin and morphine also occurs in mice, the effects of pretreatment with intrathecal (i.t.) and i.c.v. beta-funaltrexamine (beta-FNA) on analgesic response induced by i.c.v. and i.t. beta-endorphin and morphine were studied in mice. beta-FNA (2.5 micrograms) was injected i.t. or i.c.v. 24 hr before beta-endorphin or morphine administration and hot-plate and tail-flick responses were measured. Intrathecal beta-FNA attenuated i.c.v. beta-endorphin- but not i.c.v. morphine-induced analgesia. On the other hand, i.t. beta-FNA blocked both i.t. beta-endorphin- and morphine-induced analgesia, but was more effective in blocking the effects of i.t. morphine than beta-endorphin. At the supraspinal sites, beta-FNA administered i.c.v. was found to antagonize i.c.v. morphine-induced analgesia but not i.c.v. beta-endorphin-induced analgesia. The present results in mice are consistent with previous studies in rats and indicate that beta-endorphin and morphine activate different supraspinal opioid receptors. Also, analgesia produced by these two opioids resulted from activation of different descending pain inhibitory systems. The spinal endorphinergic system was involved in the production of i.c.v. beta-endorphin-, but not morphine-induced analgesia.

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↗

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

Influence of nitrous oxide upon regional brain levels of methionine-enkephalin-like immunoreactivity in rats.

The influence of a 60-min exposure to 75% nitrous oxide/25% oxygen upon concentrations of methionine-enkephalin-like immunoreactivity (MELI) in discrete brain regions was investigated in conscious rats. Compared to room air-exposed control animals, nitrous oxide-exposed rats had 12-18% increases in MELI in the brainstem, spinal cord, hypothalamus and corpus striatum. There were no significant differences between control and nitrous oxide-exposed rats in levels of MELI in the cerebral cortex or diencephalon.

Animals↗

PubMed1986

beta-Endorphin-(1-27) inhibits the spinal beta-endorphin-induced release of Met-enkephalin.

The effect of intraventricular beta-endorphin-(1-27) on the spinal release of Met-enkephalin induced by intraventricular beta-endorphin was studied using the intrathecal superfusion technique in urethane anesthetized rats. Intraventricular injection of beta-endorphin at a dose of 15 micrograms released Met-enkephalin from the spinal cord. This release of Met-enkephalin induced by beta-endorphin was significantly reduced by beta-endorphin-(1-27), 60 micrograms, injected intraventricularly. Injection of beta-endorphin (1-27) itself did not cause any release of Met-enkephalin. The finding is in line with the previous report that beta-endorphin (1-27) inhibited the analgesia induced by beta-endorphin.

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

Stereoselective effect of beta-endorphin on the production of analgesia and the spinal release of met-enkephalin in rats.

The author has previously reported that i.c.v. beta-endorphin increases the release of immunoreactive Met-enkephalin from the spinal cord. The present studies were conducted to study the effects of beta-endorphin and its position 5 amino acid-substituted analogs on the production of analgesia and the spinal release of Met-enkephalin in rats. Analgesia was measured by tail-flick test in conscious rats, and the release of Met-enkephalin from the spinal cord was studied in urethane-anesthetized rats using a technique of spinal superfusion. beta-Endorphin (0.8-40 micrograms i.c.v.) inhibited the tail-flick response in a dose-related manner, whereas D-Met5-beta-endorphin, even at the highest dose, 40 micrograms, was unable to inhibit the tail-flick response. L- and D-Leu5-beta-endorphin inhibited the tail-flick response only at high doses, with the D-isomer being slightly more potent than the L-isomer. Human beta-endorphin (0.8-16 micrograms i.c.v.) caused a dose-dependent increase of Met-enkephalin release from the spinal cord, whereas D-Met5-beta-endorphin, even at a high dose (16 micrograms), showed no release of Met-enkephalin. Leu5-beta-endorphin and D-Leu5-beta-endorphin showed little or no release of Met-enkephalin. The results indicate that beta-endorphin shows stereoselectivity on the production of analgesia and the release of Met-enkephalin.

Analgesia↗