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The experiments were designed to determine the role of pertussis toxin-(PTX) sensitive G-proteins Gi/Go in the brain and spinal cord in antinociception induced by epsilon-opioid receptor agonist beta-endorphin (beta-EP) and mu-opioid receptor agonist morphine. The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with PTX on antinociception induced by morphine, beta-endorphin (beta-EP) and other selective opioid receptor agonists given i.c.v. or i.t. were studied in male ICR mice. Antinociception was assessed by the tail-flick and hot-plate tests. An i.c.v. pretreatment with PTX (0.5 microgram) caused a time- and dose-dependent attenuation of the tail-flick and hot-plate inhibition induced by i.c.v.-challenged morphine-induced antinociception. However, the same pretreatment with PTX did not affect the antinociception induced by i.c.v.-administered beta-EP. The tail-flick and hot-plate inhibition induced by selective mu-, delta- and kappa-opioid receptor agonist, DAMGO, [D-Ala2]deltorphin II and U50,488H, respectively, given i.c.v. was also attenuated by the i.c.v. pretreatment with PTX. An i.t. pretreatment with PTX (0.5 microgram) blocked markedly the tail-flick inhibition induced by morphine and beta-EP given i.c.v. However, the same treatment did not affect the hot-plate inhibition induced by beta-EP and attenuated, to a lesser degree, the hot-plate inhibition induced by morphine given i.c.v. An i.t. pretreatment with PTX blocked the tail-flick inhibition induced by selective delta 2-, alpha 2 and 5-HT receptor agonist [D-Ala2]deltorphin, norepinephrine and 5-HT, respectively, given i.t. Our results indicate that the antinociception induced by mu-, delta-, kappa-opioid receptor agonists given supraspinally is mediated by respectively opioid receptors that are coupled to PTX-sensitive Gi/Go proteins at the supraspinal sites and subsequently mediated by the activation of PTX-sensitive Gi/Go coupled receptors in the spinal cord. However, the antinociception induced by beta-EP given supraspinally is mediated by the PTX-resistant epsilon-opioid receptors at the supraspinal sites and subsequently activation of the delta 2-opioid receptors in the spinal cord that is sensitive to the pretreatment with PTX.

We have previously demonstrated that the antinociception induced by morphine and beta-endorphin given intracerebroventricularly (i.c.v.) is mediated by the stimulation of respective mu- and epsilon-opioid receptors. The effects of i.c.v. pretreatment with pertussis toxin on the antinociception induced by morphine and beta-endorphin given i.c.v. were studied in male ICR mice. Antinociception was assessed by the tail-flick and hot-plate tests. Pretreatment with pertussis toxin (0.5 microgram) given i.c.v. 96 h earlier blocks the antinociception induced by i.c.v. administered morphine in both tail-flick and hot-plate tests. The same pretreatment did not affect the antinociception induced by i.c.v. administered beta-endorphin. Our results indicate that morphine-, but not beta-endorphin-induced antinociception is mediated by pertussis toxin sensitive G-proteins.

The antinociception induced by beta-endorphin given supraspinally has been previously demonstrated to be mediated by the stimulation of epsilon-, but not mu-, delta- or kappa-opioid receptors in rats and mice. The present study was designed to determine what types of opioid receptors in the spinal cord are involved in the antinociception induced by intrathecally (i.t.) administered beta-endorphin. Antinociception was assessed by the tail-flick test in male Sprague-Dawley rats. CTOP (0.9-6.6 nmol), a selective mu-opioid receptor antagonist, or nor-BNI(13.6-95.3 nmol), a selective kappa-opioid receptor antagonist, given i.t. dose-dependently reversed i.t. administered beta-endorphin-induced inhibition of the tail-flick response. On the other hand, naltrindole (6.6-44.4 nmol), a selective delta-opioid receptor antagonist, or beta-endorphin (1-27) (1-6.7 nmol), a selective epsilon-opioid receptor antagonist given i.t., did not antagonize the inhibition of the tail-flick response induced by i.t. administered beta-endorphin. The results are consistent with the previous study in mice [Tseng LF and Collins KA (1992) Eur J Pharmacol 214: 59-65] that the antinociception induced by beta-endorphin given i.t. is mediated by the stimulation of mu- and kappa-, but not delta- and epsilon-opioid receptors.

The antinociception induced by beta-endorphin given supraspinally has been previously demonstrated to be mediated by the release of [Met5]enkephalin acting on delta-opioid receptors in the spinal cord. The present study was designed to determine what type of opioid receptors in the spinal cord is involved in beta-endorphin-induced antinociception in the rat. Antinociception was induced by beta-endorphin (0.6 nmol) given into nucleus raphe obscurus and was assessed by the tail-flick test in pentobarbital-anesthesized rats. Naltriben (0.6-6.0 nmol), a selective delta 2-opioid receptor antagonist, given intrathecally dose-dependently attenuated beta-endorphin-induced inhibition of the tail-flick response. On the other hand, 7-benzylidene naltrexone (2.1-64.3 nmol), CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, 0.09-2.8 nmol), or nor-binaltorphimine (1.4-40.8 nmol), selective delta 1-, mu-, and kappa-opioid receptor antagonists, respectively, did not block beta-endorphin-induced antinociception. The results of present study in rats are consistent with previous experiments in mice indicating that spinal delta 2-, but not delta 1-, mu- or kappa-opioid receptors are involved in beta-endorphin-induced inhibition of the tail-flick response.

The antinociceptive effects induced by beta-endorphin and morphine given supraspinally have been previously demonstrated to be mediated by the activation of different neural mechanisms. The present experiments were to examine the effects of intraventricular administration of beta-endorphin and morphine in mechanical paw-withdrawal and thermal tail-flick nociceptive tests in rats of 2-28 days of age. 2-4-day-old neonates were not responsive to i.c.v. injection of beta-endorphin or morphine for the inhibition of the tail-flick response. The thermal antinociceptive responses induced by beta-endorphin and morphine started to develop in 7-14-day-old rats and continued to increase at 21-28 days. The inhibition of the mechanical paw-withdrawal response to beta-endorphin was already present in 2-day-old rats and morphine in 4-day-old rats. The mechanical antinociception progressively increased and reached a plateau at 7 days of age for beta-endorphin and 28 days of age for morphine. beta-Endorphin was found to be more efficacious than morphine in producing mechanical antinociception. The results demonstrate that beta-endorphin- and morphine-induced antinociception to mechanical and thermal stimuli develops differently and are consistent with the hypothesis that two descending pain inhibitory systems activated by beta-endorphin and morphine are differentially developed.

The antinociception induced by supraspinally administered beta-endorphin is mediated by the release of Met-enkephalin and subsequent stimulation of delta-opioid receptors from the spinal cord in mice. Repeated intrathecal administration of an antisense oligodeoxynucleotide against delta-opioid receptors selectively attenuated i.c.v. administered beta-endorphin-induced antinociception without any effect on the antinociception induced by mu-opioid receptor agonists, morphine and DAMGO, or kappa-opioid receptor agonists, U50,488H. A random sequence oligodeoxynucleotide was inactive against beta-endorphin-induced antinociception. The study confirms previous findings that the antinociception induced by beta-endorphin is mediated by the stimulation of the delta-opioid receptors in the spinal cord.

The effects of subcutaneous morphine pellet-implantation on antinociception induced by intracerebroventricular (i.c.v.) administration of beta-endorphin or morphine and intrathecal (i.t.) administration of morphine, [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ala2,NMePhe4,Gly5-ol]enkephalin (DAMGO), serotonin or norepinephrine were studied in male ICR mice. The tail-flick and hot-plate responses were used for antinociceptive tests. The ED50 values for i.c.v. administered morphine for antinociception in morphine pellet-implanted mice were increased from 3.3- and 2.2-fold at 0 h to 14.2- and 19.0-fold at 4 h and declined to 4.8- and 3.0-fold at 8 h after pellet removal in the tail-flick and hot-plate tests, respectively. On the other hand, the ED50 values for i.c.v. administered beta-endorphin for antinociception were only slightly increased (1.7- to 5.1-fold increases) throughout the same time course. The inhibition of the tail-flick response induced by i.t. injection of morphine, DPDPE and serotonin, but not norepinephrine or DAMGO, was attenuated in morphine pellet-implanted mice. These findings are consistent with previous studies indicating that different neuronal mechanisms are involved in morphine- and beta-endorphin-induced antinociception.

The antinociception induced by beta-endorphin given intracerebroventricularly (i.c.v.) has been previously demonstrated to be mediated by the release of Met-enkephalin and subsequent stimulation of delta receptors in the spinal cord for antinociception. The present study was designed to determine what type of opioid receptor, delta 1 or delta 2, in the spinal cord is involved in i.c.v. beta-endorphin-induced antinociception. Antinociception was assessed by the tail-flick test in male ICR mice. NTB (0.2-20 nmol) and NTI (0.22-2.2 nmol), selective delta 2 receptor antagonists, given intrathecally (i.t.) dose-dependently attenuated i.c.v. beta-endorphin-induced inhibition of the tail-flick response. On the other hand, BNTX (0.02-2.2 nmol), a selective delta 1 receptor antagonist, given i.t., did not block i.c.v. beta-endorphin-induced antinociception. The tail-flick inhibition induced by DAMGO, a mu receptor agonist, or U50,488H, a kappa receptor agonist, was not blocked by i.t. BNTX, NTB or NTI. It is concluded that delta 2 but not delta 1 receptors in the spinal cord are involved in i.c.v. beta-endorphin-induced antinociception.

The inhibition of the tail-flick response induced by beta-endorphin given i.c.v. has been demonstrated to be mediated by the stimulation of epsilon- but not mu-, delta- or kappa-opioid receptors. beta-Endorphin given i.t. also inhibited the tail-flick response. The present studies were designed to determine what types of opioid receptors in the spinal cord were involved in i.t. beta-endorphin-induced tail-flick inhibition. Blockade of kappa-opioid receptors by coadministration of nor-binaltorphimine or Win 44,441-3 with beta-endorphin given i.t. dose dependently inhibited i.t. beta-endorphin-induced inhibition of the tail-flick response. Blockade of mu-opioid receptors by i.t. coadministration of D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH2 with beta-endorphin blocked i.t. beta-endorphin-induced inhibition of the tail-flick response. I.t. injection of delta-opioid receptors antagonists, ICI 174,864 and naltrindole, or epsilon-opioid receptor antagonist, beta-endorphin-(1-27), did not affect inhibition of the tail-flick response induced by beta-endorphin given i.t. Blockade of alpha 2-adrenoceptors and 5-HT receptors by i.t. injection of yohimbine and methysergide, respectively, also did not affect inhibition of the tail-flick response induced by beta-endorphin given i.t. The results indicate that the inhibition of the tail-flick response induced by beta-endorphin given i.t. is mediated by the stimulation of kappa- and mu-opioid receptors but not delta- and epsilon-opioid receptors, alpha 2-adrenoceptors or 5-HT receptors.

The effects of sulfated cholecystokinin octapeptide (CCK8s) given intrathecally (i.t.) or intracerebroventricularly (i.c.v.) on inhibition of the tail-flick and paw-licking hot-plate responses induced by beta-endorphin, morphine, D-Ala2-N-Me-Phe4-Gly-ol-Enkephalin (DAMGO) and D-Pen2-D-Pen5-Enkephalin (DPDPE), given i.t. or i.c.v., were studied in male ICR mice. CCK8s (1 ng) given i.t. effectively antagonized inhibition of the tail-flick response induced by i.c.v. administered beta-endorphin (2 micrograms) and DPDPE (10 micrograms) but not morphine (4 micrograms) or DAMGO (0.02 microgram). However, CCK8s given i.t. did not affect inhibition of the hot-plate response induced by any of the opioid agonists. CCK8s (0.2-40 ng) in combination with beta-endorphin (2 micrograms) or morphine (4 micrograms) given i.c.v. did not affect beta-endorphin- or morphine-induced inhibition of the tail-flick and hot-plate responses. CCK8s and its fragments given i.t. attenuated i.c.v. beta-endorphin-induced tail-flick inhibition with different potencies and efficacies. CCK8s was the most potent compound in antagonizing i.c.v. beta-endorphin-induced tail-flick inhibition. The rank order of potencies was CCK8s greater than CCK(27-33) much greater than caerulein. All three compounds were efficacious, whereas CCK(30-33) was not, in antagonizing beta-endorphin-induced tail-flick inhibition. Intrathecal administration of CCK8s (1 ng) significantly attenuated the tail-flick inhibition induced by i.t. beta-endorphin (0.5-1 microgram) and DPDPE (5 micrograms) but not morphine (0.5-1 microgram), DAMGO (5 ng), norepinephrine (5 ng) or serotonin (16 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

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)