The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Kazutaka Ikeda - One of the best experts on this subject based on the ideXlab platform.
-
(-)-Pentazocine induces visceral chemical Antinociception, but not thermal, mechanical, or somatic chemical Antinociception, in μ-opioid receptor knockout mice
Molecular pain, 2011Co-Authors: Soichiro Ide, Masabumi Minami, George R. Uhl, Masamichi Satoh, Ichiro Sora, Kazutaka IkedaAbstract:Background: (-)-Pentazocine has been hypothesized to induce analgesia via the -opioid (KOP) receptor, although the involvement of other opioid receptor subtypes in the effects of pentazocine remains unknown. In this study, we investigated the role of the μ-opioid (MOP) receptor in thermal, mechanical, and chemical Antinociception induced by (-)-pentazocine using MOP receptor knockout (MOP-KO) mice. Results: (-)-Pentazocine-induced thermal Antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice compared with wildtype mice. The results obtained from the (-)-pentazocine-induced mechanical and somatic chemical Antinociception experiments, which used the hind-paw pressure and formalin tests, were similar to the results obtained from the thermal Antinociception experiments in these mice. However, (-)-pentazocine retained its ability to induce significant visceral chemical Antinociception, assessed by the writhing test, in homozygous MOP-KO mice, an effect that was completely blocked by pretreatment with nor-binaltorphimine, a KOP receptor antagonist. In vitro binding and cyclic adenosine monophosphate assays showed that (-)-pentazocine possessed higher affinity for KOP and MOP receptors than for δ-opioid receptors. Conclusions: The present study demonstrated the abolition of the thermal, mechanical, and somatic chemical antinociceptive effects of (-)-pentazocine and retention of the visceral chemical antinociceptive effects of (-)-pentazocine in MOP-KO mice. These results suggest that the MOP receptor plays a pivotal role in thermal, mechanical, and somatic chemical Antinociception induced by (-)-pentazocine, whereas the KOP receptor is involved in visceral chemical Antinociception induced by (-)-pentazocine.
-
Abolished thermal and mechanical Antinociception but retained visceral chemical Antinociception induced by butorphanol in μ-opioid receptor knockout mice
Neuropharmacology, 2008Co-Authors: Soichiro Ide, Masabumi Minami, Kumatoshi Ishihara, George R. Uhl, Masamichi Satoh, Ichiro Sora, Kazutaka IkedaAbstract:Abstract Butorphanol is hypothesized to induce analgesia via opioid pathways, although the precise mechanisms for its effects remain unknown. In this study, we investigated the role of the μ-opioid receptor (MOP) in thermal, mechanical, and visceral chemical Antinociception induced by butorphanol using MOP knockout (KO) mice. Butorphanol-induced thermal Antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice compared with wildtype mice. The results obtained from our butorphanol-induced mechanical Antinociception experiments, assessed by the Randall–Selitto test, were similar to the results obtained from the thermal Antinociception experiments in these mice. Interestingly, however, butorphanol retained its ability to induce significant visceral chemical Antinociception, assessed by the writhing test, in homozygous MOP-KO mice. The butorphanol-induced visceral chemical Antinociception that was retained in homozygous MOP-KO mice was completely blocked by pretreatment with nor-binaltorphimine, a κ-opioid receptor (KOP) antagonist. In vitro binding and cyclic adenosine monophosphate assays also showed that butorphanol possessed higher affinity for KOPs and MOPs than for δ-opioid receptors. These results molecular pharmacologically confirmed previous studies implicating MOPs, and partially KOPs, in mediating butorphanol-induced analgesia.
Jiantian Qiao - One of the best experts on this subject based on the ideXlab platform.
-
involvement of endogenous opioids and atp sensitive potassium channels in the mediation of apomorphine induced Antinociception at the spinal level a study using emg planimetry of flexor reflex in rats
Brain Research Bulletin, 1999Co-Authors: Weimin Hu, Yuming Kang, Jiantian QiaoAbstract:Abstract The effects of intrathecally (i.t.) administered naloxone or glibenclamide, a blocker of adenosine triphosphate-sensitive potassium (K ATP ) channels, on the Antinociception produced by i.t. apomorphine were observed by an integrated electromyogram measurement of hindlimb flexor reflex in lightly pentobarbital-anesthetized rats. The results showed that i.t. apomorphine produced a significant and dose-dependent Antinociception and that the Antinociception produced by i.t. apomorphine could be blocked dose dependently by i.t. naloxone or glibenclamide. The results suggest that endogenous opioids and ATP-sensitive potassium channels might be sequentially involved in the mediation of apomorphine-induced Antinociception at the spinal level.
-
Involvement of endogenous opioids and ATP-sensitive potassium channels in the mediation of carbachol-induced Antinociception at the spinal level: a behavioral study in rats
Brain research, 1997Co-Authors: Yuming Kang, Ce Zhang, Jiantian QiaoAbstract:The effects of intrathecally administered (i.t.) atropine, glibenclamide, a blocker of ATP-sensitive potassium channels, or naloxone on the Antinociception produced by i.t. carbachol or morphine were observed in rats by tail-flick (TF) test. The results showed that: (1) i.t. carbachol produced a dose-dependent Antinociception and it could be antagonized by i.t. atropine; (2) the Antinociception produced by i.t. carbachol could be blocked dose-dependently by i.t. glibenclamide or i.t. naloxone; (3) the Antinociception produced by i.t. morphine could be blocked dose-dependently by i.t. glibenclamide, but not by i.t. atropine. The results suggest that the Antinociception produced by activation of muscarinic receptors at the spinal level might be mediated by endogenous opioids and ATP-sensitive potassium channels in a cascade form.
-
Adenosine and opiate-like substances mediates Antinociception at the spinal cord
Brain research, 1995Co-Authors: Shou Wei Yang, Jiantian Qiao, Zhi Hua Zhang, Jin Yuan Chen, Yi Fang Xie, Nachum DafnyAbstract:The effects of intrathecally administered naloxone or aminophylline on the Antinociception produced by intrathecal NE, 5-HT, morphine or adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA) were observed in rats using the tail-flick test. The results show that: (1) the Antinociception produced by NE with doses of 0.5 or 1.0 nmol could be completely blocked by both naloxone (240 nmol) and aminophylline (120 nmol); (2) neither naloxone (240 nmol) nor aminophylline (120 nmol) could alter the Antinociception produced by 5-HT with doses of 60 or 120 nmol; and (3) the Antinociception produced by morphine (0.5 nmol) could be blocked by both naloxone (240 nmol) and aminophylline (120 nmol), while the Antinociception by NECA (0.5 nmol) could be blocked only by aminophylline (120 nmol), but not by naloxone (240 nmol). The results suggest that opiate-like substances (OLS) and adenosine are involved in the mediation of the NE-produced Antinociception, but not in 5-HT-produced Antinociception. Results also suggest that NE, OLS and adenosine may act in a sequential order in the performance of NE-induced Antinociception at the spinal level.
-
Morphine and norepinephrine-induced Antinociception at the spinal level is mediated by adenosine.
Neuroreport, 1994Co-Authors: Shou Wei Yang, Jiantian Qiao, Zhi Hua Zhang, Jin Yuan Chen, Yi Fang Xie, Nachum DafnyAbstract:The purpose of this study was to examine whether adenosine or serotonin is involved in mediation of the Antinociception produced by norepinephrine at the spinal cord level. Aminophylline, an adenosine receptor antagonist and naloxone given intrathecally (i.t.) were used to test the Antinociception produced by i.t. norepinephrine, serotonin, morphine or the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) by using the tail-flick assay in rats. It was observed that (1) aminophylline blocked the Antinociception produced by norepinephrine, but exhibited no effect on the Antinociception produced by serotonin, (2) aminophylline blocked the Antinociception produced by morphine similarly to naloxone, (3) aminophylline blocked the Antinociception produced by NECA and (4) naloxone failed to block the Antinociception produced by NECA and serotonin. The results suggest that adenosine is involved in mediation of the norepinephrine-produced Antinociception at the spinal level and that norepinephrine and adenosine may act in a sequential manner in norepinephrine-induced Antinociception.
Michael M Morgan - One of the best experts on this subject based on the ideXlab platform.
-
Enhanced Antinociception with repeated microinjections of apomorphine into the periaqueductal gray of male and female rats.
Behavioural Pharmacology, 2017Co-Authors: Shauna M. Schoo, Erin N Bobeck, Michael M MorganAbstract:Dopamine neurons in the ventrolateral periaqueductal gray (PAG) have been reported to contribute to Antinociception. The objective of this study was to determine how this dopamine-mediated Antinociception differs from what is known about morphine-induced Antinociception. Microinjection of the dopamine receptor agonist apomorphine into the PAG produced a dose-dependent increase in hot plate latency and a decrease in open field activity that was greater in male than in female rats. The peak antinociceptive effect occurred 5 min after apomorphine administration. Surprisingly, the antinociceptive potency of apomorphine was enhanced following systemic administration of the opioid receptor antagonist naloxone in male, but not in female rats. The antinociceptive potency of microinjecting apomorphine into the ventrolateral PAG in male and female rats was also enhanced following twice-daily injections for 2 days. The characteristics of apomorphine-induced Antinociception differ from previous reports of morphine Antinociception following PAG microinjections in that morphine Antinociception peaks at 15 min, is blocked by naloxone, and is susceptible to tolerance with repeated administration. These results indicate that apomorphine-induced Antinociception is distinct from opioid-induced Antinociception, and that dopamine receptor agonists may provide a novel approach to pain modulation.
-
Opioid Selective Antinociception Following Microinjection Into the Periaqueductal Gray of the Rat
The journal of pain : official journal of the American Pain Society, 2014Co-Authors: Michael M Morgan, Rachel A. Reid, Thomas M. Stormann, Nathan LautermilchAbstract:Abstract Morphine and fentanyl produce Antinociception in part by binding to mu-opioid receptors in the periaqueductal gray (PAG). The present study tested the hypothesis that the PAG also contributes to the antinociceptive effects of other commonly used opioids (oxycodone, methadone, and buprenorphine). Microinjection of high doses of oxycodone (32–188 μg/.4 μL) into the ventrolateral PAG of the rat produced a dose-dependent increase in hot plate latency. This Antinociception was evident within 5 minutes and nearly gone by 30 minutes. In contrast, no Antinociception was evident following microinjection of methadone or buprenorphine into the ventrolateral PAG despite use of a wide range of doses and test times. Antinociception was evident following subsequent microinjection of morphine into the same injection sites or following systemic administration of buprenorphine, demonstrating that the injections sites and drugs could support Antinociception. Antinociception to systemic, but not PAG, administration of buprenorphine occurred in both male and female rats. These and previous data demonstrate that the mu-opioid receptor signaling pathway for Antinociception in the PAG is selectively activated by some commonly used opioids (eg, morphine, fentanyl, and oxycodone) but not others (eg, methadone or buprenorphine). The fact that methadone and buprenorphine produce Antinociception following systemic administration demonstrates that mu-opioid receptor signaling varies depending on location in the nervous system. Perspective This study demonstrates that the PAG contributes to the antinociceptive effects of some commonly used opioids (morphine, fentanyl, and oxycodone) but not others (methadone or buprenorphine). Such functional selectivity in PAG-mediated opioid Antinociception helps explain why the analgesic profile of opioids is so variable.
-
Opioid receptor internalization contributes to dermorphin-mediated Antinociception.
Neuroscience, 2010Co-Authors: Tara A. Macey, Erin N Bobeck, Susan L. Ingram, Deborah M. Hegarty, Sue A. Aicher, Seksiri Arttamangkul, Michael M MorganAbstract:Abstract Microinjection of opioids into the ventrolateral periaqueductal gray (vlPAG) produces Antinociception in part by binding to mu-opioid receptors (MOPrs). Although both high and low efficacy agonists produce Antinociception, low efficacy agonists such as morphine produce limited MOPr internalization suggesting that MOPr internalization and signaling leading to Antinociception are independent. This hypothesis was tested in awake, behaving rats using DERM-A594, a fluorescently labeled dermorphin analog, and internalization blockers. Microinjection of DERM-A594 into the vlPAG produced both Antinociception and internalization of DERM-A594. Administration of the irreversible opioid receptor antagonist beta-chlornaltrexamine (beta-CNA) prior to DERM-A594 microinjection reduced both the antinociceptive effect and the number of DERM-A594 labeled cells demonstrating that both effects are opioid receptor-mediated. Pretreatment with the internalization blockers dynamin dominant-negative inhibitory peptide (dynamin-DN) and concanavalinA (ConA) attenuated both DERM-A594 internalization and Antinociception. Microinjection of dynamin-DN and ConA also decreased the antinociceptive potency of the unlabeled opioid agonist dermorphin when microinjected into the vlPAG as demonstrated by rightward shifts in the dose-response curves. In contrast, administration of dynamin-DN had no effect on the antinociceptive effect of microinjecting the GABA A receptor antagonist bicuculline into the vlPAG. The finding that dermorphin-induced Antinociception is attenuated by blocking receptor internalization indicates that key parts of opioid receptor-mediated signaling depend on internalization.
-
Drug dependent sex-differences in periaqueducatal gray mediated Antinociception in the rat.
Pain, 2009Co-Authors: Erin N Bobeck, Amy L Mcneal, Michael M MorganAbstract:Mu-opioid receptor (MOPr) agonists, such as morphine, produce greater Antinociception in male compared to female rats. The ventolateral periaqueductal gray (vlPAG) appears to contribute to this sex-difference despite fewer vlPAG output neurons projecting to the rostral ventromedial medulla in male compared to female rats. This greater projection in female rats suggests that non-opioid activation of vlPAG output neurons should produce greater Antinociception in female compared to male rats. This hypothesis was tested by comparing the time course and antinociceptive potency of microinjecting MOPr agonists (morphine, DAMGO, fentanyl) and non-opioid compounds (bicuculline, kainic acid) into the vlPAG of female and male rats. Microinjection of morphine or DAMGO produced Antinociception that had a slow onset (peak from 15 to 30min) and long duration (60min) compared to the Antinociception produced following microinjection of fentanyl, bicuculline, or kainic acid (peak effect at 3min; duration less than 30min). No sex-differences in the time courses were evident. All five compounds caused a dose-dependent Antinociception when microinjected into the vlPAG. Antinociceptive potency was significantly greater in male compared to female rats following microinjection of morphine, DAMGO, and bicuculline, but not following microinjection of fentanyl or kainic acid. In no case did activation of the vlPAG produce greater antinocicepiton in female compared to male rats. These findings demonstrate that the vlPAG can produce comparable Antinociception in female and male rats, but Antinociception produced by inhibition of GABAergic neurons (whether by morphine or the GABA(A) receptor antagonist bicuculline) produces greater Antinociception in males.
Soichiro Ide - One of the best experts on this subject based on the ideXlab platform.
-
(-)-Pentazocine induces visceral chemical Antinociception, but not thermal, mechanical, or somatic chemical Antinociception, in μ-opioid receptor knockout mice
Molecular pain, 2011Co-Authors: Soichiro Ide, Masabumi Minami, George R. Uhl, Masamichi Satoh, Ichiro Sora, Kazutaka IkedaAbstract:Background: (-)-Pentazocine has been hypothesized to induce analgesia via the -opioid (KOP) receptor, although the involvement of other opioid receptor subtypes in the effects of pentazocine remains unknown. In this study, we investigated the role of the μ-opioid (MOP) receptor in thermal, mechanical, and chemical Antinociception induced by (-)-pentazocine using MOP receptor knockout (MOP-KO) mice. Results: (-)-Pentazocine-induced thermal Antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice compared with wildtype mice. The results obtained from the (-)-pentazocine-induced mechanical and somatic chemical Antinociception experiments, which used the hind-paw pressure and formalin tests, were similar to the results obtained from the thermal Antinociception experiments in these mice. However, (-)-pentazocine retained its ability to induce significant visceral chemical Antinociception, assessed by the writhing test, in homozygous MOP-KO mice, an effect that was completely blocked by pretreatment with nor-binaltorphimine, a KOP receptor antagonist. In vitro binding and cyclic adenosine monophosphate assays showed that (-)-pentazocine possessed higher affinity for KOP and MOP receptors than for δ-opioid receptors. Conclusions: The present study demonstrated the abolition of the thermal, mechanical, and somatic chemical antinociceptive effects of (-)-pentazocine and retention of the visceral chemical antinociceptive effects of (-)-pentazocine in MOP-KO mice. These results suggest that the MOP receptor plays a pivotal role in thermal, mechanical, and somatic chemical Antinociception induced by (-)-pentazocine, whereas the KOP receptor is involved in visceral chemical Antinociception induced by (-)-pentazocine.
-
Abolished thermal and mechanical Antinociception but retained visceral chemical Antinociception induced by butorphanol in μ-opioid receptor knockout mice
Neuropharmacology, 2008Co-Authors: Soichiro Ide, Masabumi Minami, Kumatoshi Ishihara, George R. Uhl, Masamichi Satoh, Ichiro Sora, Kazutaka IkedaAbstract:Abstract Butorphanol is hypothesized to induce analgesia via opioid pathways, although the precise mechanisms for its effects remain unknown. In this study, we investigated the role of the μ-opioid receptor (MOP) in thermal, mechanical, and visceral chemical Antinociception induced by butorphanol using MOP knockout (KO) mice. Butorphanol-induced thermal Antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice compared with wildtype mice. The results obtained from our butorphanol-induced mechanical Antinociception experiments, assessed by the Randall–Selitto test, were similar to the results obtained from the thermal Antinociception experiments in these mice. Interestingly, however, butorphanol retained its ability to induce significant visceral chemical Antinociception, assessed by the writhing test, in homozygous MOP-KO mice. The butorphanol-induced visceral chemical Antinociception that was retained in homozygous MOP-KO mice was completely blocked by pretreatment with nor-binaltorphimine, a κ-opioid receptor (KOP) antagonist. In vitro binding and cyclic adenosine monophosphate assays also showed that butorphanol possessed higher affinity for KOPs and MOPs than for δ-opioid receptors. These results molecular pharmacologically confirmed previous studies implicating MOPs, and partially KOPs, in mediating butorphanol-induced analgesia.
Frank Porreca - One of the best experts on this subject based on the ideXlab platform.
-
Antinociception depends on the presence of G protein gamma2-subunits in brain.
European journal of pharmacology, 2005Co-Authors: Eva V. Varga, Keiko Hosohata, Todd W. Vanderah, Frank Porreca, William R. Roeske, Dariusz Borys, Edita Navratilova, Anders Nylen, Henry I. YamamuraAbstract:We have shown previously [Hosohata, K., Logan, J.K., Varga, E., Burkey, T.H., Vanderah, T.W., Porreca, F., Hruby, V.J., Roeske, W.R., Yamamura, H.I., 2000. The role of the G protein gamma2 subunit in opioid Antinociception in mice. Eur. J. Pharmacol. 392, R9-R11] that intracerebroventricular (i.c.v.) treatment of mice with a phosphorothioate oligodeoxynucleotide antisense to the gamma2 subunit (Ggamma2) of the heterotrimeric G proteins (antisense ODN) significantly attenuates Antinociception by a delta-opioid receptor agonist. In the present study, we examined the involvement of Ggamma2 in Antinociception mediated by other (mu- or kappa-opioid, cannabinoid, alpha2-adrenoreceptor) analgesic agents in a warm (55 degrees C) water tail-flick test in mice. Interestingly, i.c.v. treatment with the antisense ODN attenuated Antinociception by each analgesic agent. Missense phosphorothioate oligodeoxynucleotide treatment, on the other hand, had no effect on Antinociception mediated by these agonists. The antinociceptive response recovered in 6 days after the last antisense ODN injection, indicating a lack of nonspecific tissue damage in the animals. These results suggest a pervasive role for the G protein gamma2 subunits in supraspinal Antinociception.
-
CB2 cannabinoid receptor-mediated peripheral Antinociception.
Pain, 2001Co-Authors: T. Philip Malan, Todd W. Vanderah, Frank Porreca, Mohab M. Ibrahim, Hongfeng Deng, Qian Liu, Heriberto P. Mata, Alexandros MakriyannisAbstract:Abstract Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB 1 receptor in the production of Antinociception. However, the capacity of CB 2 receptors, which are located outside the central nervous system (CNS), to produce Antinociception is not known. Using AM1241, a CB 2 receptor-selective agonist, we demonstrate that CB 2 receptors produce Antinociception to thermal stimuli. Injection of AM1241 in the hindpaw produced Antinociception to a stimulus applied to the same paw. Injection of an equivalent dose of AM1241 into the paw contralateral to the side of testing did not. The antinociceptive actions of AM1241 were blocked by the CB 2 receptor-selective antagonist AM630, but not by the CB 1 receptor-selective antagonist AM251. AM1241 also produced Antinociception when injected systemically (intraperitoneally). The antinociceptive actions of systemic AM1241 were blocked by injection of AM630 into the paw where the thermal stimulus was applied, but not the contralateral paw. These findings demonstrate the local, peripheral nature of CB 2 cannabinoid Antinociception. AM1241 did not produce the CNS cannabinoid effects of hypothermia, catalepsy, inhibition of activity or impaired ambulation, while this tetrad of effects was produced by the mixed CB 1 /CB 2 receptor agonist WIN55,212-2. Peripheral Antinociception without CNS effects is consistent with the peripheral distribution of CB 2 receptors. CB 2 receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.
-
The role of the G protein γ2 subunit in opioid Antinociception in mice
European Journal of Pharmacology, 2000Co-Authors: Keiko Hosohata, Jennifer K Logan, Eva V. Varga, Thomas H Burkey, Todd W. Vanderah, Frank Porreca, William R. Roeske, Vladimir J. Hruby, Henry I. YamamuraAbstract:Abstract We examined the role of the γ2 subunit of G proteins (Gγ2) in the Antinociception produced by c[D-Pen2,D-Pen5]enkephalin (DPDPE) in mice. DPDPE produced 84.0±9.0% Antinociception in vehicle-treated mice. After intracerebroventricular (i.c.v.) treatment with an antisense phosphorothioate oligodeoxynucleotide to the Gγ2 subunit, DPDPE-mediated Antinociception decreased to 24.4±7.4%. The mismatch phosphorothioate oligodeoxynucleotide-treated mice showed 65.1±10.3% Antinociception, while the missense phosphorothioate oligodeoxynucleotide-treated mice showed 76.4±23.6% Antinociception by DPDPE. The reduction of analgesia in antisense phosphorothioate oligodeoxynucleotide-treated mice was significant in comparison with vehicle-treated (P
-
Etonitazene-induced Antinociception in μ1 opioid receptor deficient CXBK mice : evidence for a role for μ2 receptors in supraspinal Antinociception
Life Sciences, 1994Co-Authors: Charlene D. Connelly, Frank Porreca, Rebecca P. Martinez, James J. Schupsky, Robert B. RaffaAbstract:Abstract The prevailing view is that supraspinal μ opioid-mediated Antinociception in mice is mediated via the μ 1 subtype. The purpose of the present study was to determine if the highly μ-selective compound etonitazene could produce supraspinal (intracerebroventricular; i.c.v.) Antinociception in CXBK mice, which are deficient in brain μ 1 , but not μ 2 , opioid receptors. CXBK or normal Crl:CD-1 ® (ICR)BR mice were administered graded doses of etonitazene i.c.v. and 15 min later Antinociception was assessed by a standard radiant-heat or 55°C water tail-flick test. Etonitazene produced dose-related Antinociception that was blocked by naloxone and by β-FNA (demonstrating a μ opioid mechanism), but not by either ICI-174,864 or naltrindole (demonstrating the lack of involvement of δ opioid receptors). These findings suggest that μ 2 opioid receptors are important contributors to opioid-induced supraspinal Antinociception in mice.
-
differential antagonism of opioid delta Antinociception by d ala2 leu5 cys6 enkephalin and naltrindole 5 isothiocyanate evidence for delta receptor subtypes
Journal of Pharmacology and Experimental Therapeutics, 1991Co-Authors: Qi Jiang, Philip S. Portoghese, A. E. Takemori, M Sultana, Wayne D Bowen, Henry I Mosberg, Frank PorrecaAbstract:The present study has investigated the direct opioid delta receptor-mediated Antinociception produced by i.c.v. administration of the highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II, as well as that of the less delta-selective [D-Ser2,Leu5,Thr6]enkephalin (DSLET), by using two novel nonequilibrium opioid antagonists, [D-Ala2,Leu5,Cys6] enkephalin (DALCE) and naltrindole 5'-isothiocyanate (5'-NTII). At times ranging from 8 to 48 hr after a single i.c.v. pretreatment of mice with 5'-NTII, the antinociceptive effects of [D-Ala2] deltorphin II were significantly antagonized. In contrast, 5'-NTII pretreatment at times between 10 min and 24 hr failed to antagonize the antinociceptive effects of DPDPE. Previous studies have shown that pretreatment with i.c.v. DALCE produces a dose- and time-related antagonism of DPDPE, but not morphine, Antinociception. However, pretreatment with i.c.v. DALCE failed to antagonize the antinociceptive effects of [D-Ala2]deltorphin II. Similarly, i.c.v. administration of DSLET produced time- and dose-related Antinociception which was partially antagonized by either beta-funaltrexamine (beta-FNA) or by ICI 174,864 (N,N-dialyl-Tyr-Aib-Aib-Phe-Leu-OH), suggesting mixed activity at mu and delta receptors. ICI 174,864 produced essentially complete antagonism of DSLET Antinociception in beta-FNA-pretreated mice. Pretreatment with 5'-NTII (at -8 to -48 hr), blocked the Antinociception produced by DSLET in control or in beta-FNA-pretreated mice. In contrast, pretreatment with DALCE failed to antagonize the Antinociception produced by i.c.v. DSLET in either control or in beta-FNA-pretreated mice.(ABSTRACT TRUNCATED AT 250 WORDS)