The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform
James M Fujimoto - One of the best experts on this subject based on the ideXlab platform.
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Nonopioidergic Mechanism Mediating Morphine-Induced Antianalgesia in the Mouse Spinal Cord
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Hsiang-en Wu, James M Fujimoto, Jonathan Thompson, Randy J. Leitermann, Leon F. TsengAbstract:Intrathecal (i.t.) pretreatment with a low dose (0.3 nmol) of morphine causes an attenuation of i.t. morphine-produced analgesia; the phenomenon has been defined as morphine-induced antianalgesia. The opioid-produced analgesia was measured with the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with low dose (0.3 nmol) of morphine time dependently attenuated i.t. morphine-produced (3.0 nmol) TF inhibition and reached a maximal effect at 45 min. Intrathecal pretreatment with morphine (0.009–0.3 nmol) for 45 min also dose dependently attenuated morphine-produced TF inhibition. The i.t. morphine-induced antianalgesia was dose dependently blocked by the nonselective μ-opioid receptor antagonist (-)-naloxone and by its nonopioid enantiomer (+)-naloxone, but not by endomorphin-2-sensitive μ-opioid receptor antagonist 3-methoxynaltrexone. Blockade of δ-opioid receptors, κ-opioid receptors, and N -methyl-d-aspartate (NMDA) receptors by i.t. pretreatment with naltrindole, nor-binaltorphimine, and (-)-5-methyl-10,11-dihydro-5 H -dibenzo[ a , d ]cyclohepten-5,10-imine maleate (MK-801), respectively, did not affect the i.t. morphine-induced antianalgesia. Intrathecal pretreatment with antiserum against dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, β-endorphin, cholecystokinin, or substance P also did not affect the i.t. morphine-induced antianalgesia. The i.t. morphine pretreatment also attenuated the TF inhibition produced by opioid μagonist [d-Ala2, N -Me-Phe4,Gly-ol5]-enkephalin, δ-agonist deltorphin II, and κ-agonist U50,488H. It is concluded that low doses (0.009–0.3 nmol) of morphine given i.t. activate an Antianalgesic system to attenuate opioid μ-, δ-, and κ-agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid μ-, δ-, or κ-receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, β-endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.
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Nociceptin and dynorphin A(1-17) produce antianalgesia through independent systems in mice.
Life Sciences, 2002Co-Authors: Jodie J. Rady, James M FujimotoAbstract:Abstract The administration of dynorphin A(1-17), Dyn, intrathecally (i.t.) or of nociceptin, intracerebroventricularly (i.c.v.) produces Antianalgesic actions against i.t. morphine in the tail flick test in mice. The Antianalgesic action of nociceptin is mediated by spinal PGE 2 and attenuated by i.t. PGD 2 or indomethacin. The Dyn response is mediated by release of IL 1β in the spinal cord to activate an ascending pathway to the brain and in turn releases IL 1β in the brain which activates a descending pathway to the spinal cord. The present work investigated the possibility that the action of IL 1β in the Dyn system might release prostaglandins so that the Dyn and nociceptin Antianalgesic systems would overlap at these points. The results indicated that in the Dyn system neither the IL 1β in the spinal cord or brain implicated prostaglandin release because i.t. and i.c.v. PGD 2 and indomethacin did not affect Dyn-induced antianalgesia. In addition, nociceptin-induced antianalgesia did not involve components in the Dyn system. Thus, the Dyn and nociceptin Antianalgesic systems did not overlap and each were independent systems.
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confluence of Antianalgesic action of diverse agents through brain interleukin1β in mice
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, James M FujimotoAbstract:Spinal dynorphin A(1–17) (Dyn) has been shown previously to produce an Antianalgesic action against intrathecal morphine in the tail-flick test in CD-1 mice. This action is known to be mediated indirectly from the spinal cord through an afferent pathway that activates flumazenil-sensitive benzodiazepine receptors in the brain and a descending circuit back down to the spinal cord sequentially involving cholecystokinin, leu-enkephalin, and N -methyl-d-aspartate receptors to produce antianalgesia. Interleukin (IL)-1β is also known to act on peripheral afferent nerves to the brain to activate a descending circuit to release spinal cholecystokinin. The present investigation determined whether IL1β is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys193-d-Pro-Thr195, an IL1β antagonist, or pretreatment with IL1βantiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1β; 10 ng of IL1β given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not Antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL1β. Activation of central benzodiazepine receptors preceded the IL1β step because flumazenil inhibited Dyn but not IL1β antianalgesia. On the other hand, [1-(2-chlorophenyl)- N -methyl- N -(1-methylpropyl)-3-isoquinolinecarboxamide], an antagonist for peripheral benzodiazepine receptors that have also recently been detected in brain tissue, inhibited IL1βantianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL1β action in the brain was linked to the linear steps in the spinal cord (cholecystokinin/ N -methyl-d-aspartate receptors) as shown by inhibition with appropriate antagonists. Thus, IL1β is a central physiological mediator in the Antianalgesic action evoked by spinal dynorphin.
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Inverse Agonist Action of Leu-Enkephalin at δ2-Opioid Receptors Mediates Spinal Antianalgesia
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, Blythe B Holmes, Leon F. Tseng, James M FujimotoAbstract:Dynorphin A(1-17) given intrathecally releases spinal cholecystokinin to produce an Antianalgesic action against spinal morphine in the tail-flick test in CD-1 mice. The present study showed that following the cholecystokinin step, a δ 2 -opioid inverse agonist action of Leu-enkephalin (LE), was involved. Pretreatment with intrathecal LE antiserum eliminated dynorphin and cholecystokinin-8s antianalgesia. A small dose of LE intrathecally produced antianalgesia that like that from dynorphin A(1-17) and cholecystokinin was eliminated by naltriben but not 7-benzylidenenaltrexone (δ 2 - and δ 1 -opioid receptor antagonist, respectively). This LE step was followed by N -methyl-d-aspartate (NMDA) receptor activation. MK801, an NMDA receptor antagonist, eliminated the antianalgesia from dynorphin A(1-17), cholecystokinin-8s, and LE. Furthermore, none of the three were effective against morphine analgesia in 129S6/SvEv mice possibly because of their deficiency in NMDA receptor response. In 129S6/SvEv mice, [d-Ser 2 ]-Leu-enkephalin-Thr analgesia was not attenuated by LE; thus, this δ 2 -analgesic agonist and LE inverse agonist action did not occur through competition at the same δ 2 -receptor in CD-1 mice. In CD-1 mice, a linear sequence of dynorphin A(1-17) → cholecystokinin → LE → NMDA receptors was indicated: cholecystokinin antiserum inhibited cholecystokinin but not LE; naltriben inhibited LE but not NMDA. The uniqueness of LE in linking dynorphin A(1-17), cholecystokinin, δ 2 -opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine.
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Antianalgesic action of nociceptin originating in the brain is mediated by spinal prostaglandin e 2 in mice
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, William B Campbell, James M FujimotoAbstract:An Antianalgesic action of intracerebroventricularly administered nociceptin was elicited against intrathecal morphine-induced antinociception in the tail-flick test in mice and investigated as a descending neuronal system for the spinal mediator involved. The nociceptin-induced antianalgesia originating in the brain was inhibited by intrathecally administered indomethacin and suggested the mediation of spinal prostaglandin. The Antianalgesic action of intracerebroventricular nociceptin was closely matched by intrathecal prostaglandin (PG) E 2 . Both shifted the dose-response curve of morphine to the right and these actions were eliminated by intrathecal PGD 2. Desensitization of the Antianalgesic action of PGE 2 by intrathecal PGE 2 pretreatment also produced cross-desensitization to the Antianalgesic action of intracerebroventricular nociceptin. Neither intracerebroventricular nociceptin nor intrathecal PGE 2 produced antianalgesia against the δ-receptor agonists given intrathecally. Thus, the Antianalgesic action of nociceptin originating in the brain is coupled to a descending neuronal pathway mediated by spinal PGE 2 .
Jodie J. Rady - One of the best experts on this subject based on the ideXlab platform.
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Nociceptin and dynorphin A(1-17) produce antianalgesia through independent systems in mice.
Life Sciences, 2002Co-Authors: Jodie J. Rady, James M FujimotoAbstract:Abstract The administration of dynorphin A(1-17), Dyn, intrathecally (i.t.) or of nociceptin, intracerebroventricularly (i.c.v.) produces Antianalgesic actions against i.t. morphine in the tail flick test in mice. The Antianalgesic action of nociceptin is mediated by spinal PGE 2 and attenuated by i.t. PGD 2 or indomethacin. The Dyn response is mediated by release of IL 1β in the spinal cord to activate an ascending pathway to the brain and in turn releases IL 1β in the brain which activates a descending pathway to the spinal cord. The present work investigated the possibility that the action of IL 1β in the Dyn system might release prostaglandins so that the Dyn and nociceptin Antianalgesic systems would overlap at these points. The results indicated that in the Dyn system neither the IL 1β in the spinal cord or brain implicated prostaglandin release because i.t. and i.c.v. PGD 2 and indomethacin did not affect Dyn-induced antianalgesia. In addition, nociceptin-induced antianalgesia did not involve components in the Dyn system. Thus, the Dyn and nociceptin Antianalgesic systems did not overlap and each were independent systems.
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confluence of Antianalgesic action of diverse agents through brain interleukin1β in mice
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, James M FujimotoAbstract:Spinal dynorphin A(1–17) (Dyn) has been shown previously to produce an Antianalgesic action against intrathecal morphine in the tail-flick test in CD-1 mice. This action is known to be mediated indirectly from the spinal cord through an afferent pathway that activates flumazenil-sensitive benzodiazepine receptors in the brain and a descending circuit back down to the spinal cord sequentially involving cholecystokinin, leu-enkephalin, and N -methyl-d-aspartate receptors to produce antianalgesia. Interleukin (IL)-1β is also known to act on peripheral afferent nerves to the brain to activate a descending circuit to release spinal cholecystokinin. The present investigation determined whether IL1β is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys193-d-Pro-Thr195, an IL1β antagonist, or pretreatment with IL1βantiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1β; 10 ng of IL1β given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not Antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL1β. Activation of central benzodiazepine receptors preceded the IL1β step because flumazenil inhibited Dyn but not IL1β antianalgesia. On the other hand, [1-(2-chlorophenyl)- N -methyl- N -(1-methylpropyl)-3-isoquinolinecarboxamide], an antagonist for peripheral benzodiazepine receptors that have also recently been detected in brain tissue, inhibited IL1βantianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL1β action in the brain was linked to the linear steps in the spinal cord (cholecystokinin/ N -methyl-d-aspartate receptors) as shown by inhibition with appropriate antagonists. Thus, IL1β is a central physiological mediator in the Antianalgesic action evoked by spinal dynorphin.
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Inverse Agonist Action of Leu-Enkephalin at δ2-Opioid Receptors Mediates Spinal Antianalgesia
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, Blythe B Holmes, Leon F. Tseng, James M FujimotoAbstract:Dynorphin A(1-17) given intrathecally releases spinal cholecystokinin to produce an Antianalgesic action against spinal morphine in the tail-flick test in CD-1 mice. The present study showed that following the cholecystokinin step, a δ 2 -opioid inverse agonist action of Leu-enkephalin (LE), was involved. Pretreatment with intrathecal LE antiserum eliminated dynorphin and cholecystokinin-8s antianalgesia. A small dose of LE intrathecally produced antianalgesia that like that from dynorphin A(1-17) and cholecystokinin was eliminated by naltriben but not 7-benzylidenenaltrexone (δ 2 - and δ 1 -opioid receptor antagonist, respectively). This LE step was followed by N -methyl-d-aspartate (NMDA) receptor activation. MK801, an NMDA receptor antagonist, eliminated the antianalgesia from dynorphin A(1-17), cholecystokinin-8s, and LE. Furthermore, none of the three were effective against morphine analgesia in 129S6/SvEv mice possibly because of their deficiency in NMDA receptor response. In 129S6/SvEv mice, [d-Ser 2 ]-Leu-enkephalin-Thr analgesia was not attenuated by LE; thus, this δ 2 -analgesic agonist and LE inverse agonist action did not occur through competition at the same δ 2 -receptor in CD-1 mice. In CD-1 mice, a linear sequence of dynorphin A(1-17) → cholecystokinin → LE → NMDA receptors was indicated: cholecystokinin antiserum inhibited cholecystokinin but not LE; naltriben inhibited LE but not NMDA. The uniqueness of LE in linking dynorphin A(1-17), cholecystokinin, δ 2 -opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine.
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Antianalgesic action of nociceptin originating in the brain is mediated by spinal prostaglandin e 2 in mice
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, William B Campbell, James M FujimotoAbstract:An Antianalgesic action of intracerebroventricularly administered nociceptin was elicited against intrathecal morphine-induced antinociception in the tail-flick test in mice and investigated as a descending neuronal system for the spinal mediator involved. The nociceptin-induced antianalgesia originating in the brain was inhibited by intrathecally administered indomethacin and suggested the mediation of spinal prostaglandin. The Antianalgesic action of intracerebroventricular nociceptin was closely matched by intrathecal prostaglandin (PG) E 2 . Both shifted the dose-response curve of morphine to the right and these actions were eliminated by intrathecal PGD 2. Desensitization of the Antianalgesic action of PGE 2 by intrathecal PGE 2 pretreatment also produced cross-desensitization to the Antianalgesic action of intracerebroventricular nociceptin. Neither intracerebroventricular nociceptin nor intrathecal PGE 2 produced antianalgesia against the δ-receptor agonists given intrathecally. Thus, the Antianalgesic action of nociceptin originating in the brain is coupled to a descending neuronal pathway mediated by spinal PGE 2 .
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Antianalgesic action of dynorphin a mediated by spinal cholecystokinin
Experimental Biology and Medicine, 1999Co-Authors: Jodie J. Rady, Blythe B Holmes, James M FujimotoAbstract:: Previous work indicates that the Antianalgesic action of pentobarbital and neurotensin administered intracerebroventricularly in mice arises from activation of a descending system to release cholecystokinin (CCK) in the spinal cord where CCK is known to antagonize morphine analgesia. Spinal dynorphin, like CCK, has an Antianalgesic action against intrathecally administered morphine. This dynorphin action is indirect; even though it is initiated in the spinal cord, it requires the involvement of an ascending pathway to the brain and a descending pathway to the spinal cord where an Antianalgesic mediator works. The aim of the present investigation was to determine if the Antianalgesic action of intrathecal dynorphin A involved spinal CCK. All drugs were administered intrathecally to mice in the tail flick test. Morphine analgesia was inhibited by dynorphin as shown by a rightward shift of the morphine dose-response curve. The effect of dynorphin was eliminated by administration of the CCK receptor antagonists lorglumide and PD135 158. One hour pretreatment with CCK antiserum also eliminated the action of dynorphin. On the other hand, the Antianalgesic action of CCK was not affected by dynorphin antiserum. Thus, CCK did not release dynorphin. Both CCK and dynorphin were Antianalgesic against DSLET but not DPDPE, delta 2 and delta 1 opioid receptor peptide agonists, respectively. The results suggest that the Antianalgesic action of dynorphin occurred through an indirect mechanism ultimately dependent on the action of spinal CCK.
J M Fujimoto - One of the best experts on this subject based on the ideXlab platform.
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elimination of the Antianalgesic action of dynorphin a by spinal transsection in barbital anesthetized mice
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Fansheng Wang, J J Rady, J M FujimotoAbstract:Previous studies in mice demonstrate that, when dynorphin A (1-17) (Dyn A) is administered intrathecally (i.t.) or released spinally (by administration of clonidine or midazolam i.c.v.), i.t. morphine-induced analgesia was reduced. The present aim was to determine whether this Antianalgesic action of Dyn A was the result of a spinal or supraspinal site of action by performing studies in spinally transsected mice. The approach was to use anesthetized, acute spinally transsected mice rather than chronic spinally transsected animals to avoid the need for long-term special animal care. The first part of the study evaluated four nonvolatile general anesthetic agents in an attempt to obtain one that did not affect the Antianalgesic action of Dyn A, the release of Dyn A, the analgesic action of i.t. morphine (inhibition of the tail-flick response) or the tail-flick latency by itself. alpha-Chloralose (120 mg/kg), urethane (1 g/kg) and pentobarbital (20 or 40 mg/kg) given i.p. did not meet one or more of these requirements. Barbital 400 mg/kg i.p. met the requirements. In the second part of the study, barbital combined with halothane anesthesia was used to perform acute spinal transsection experiments. As in sham controls, the analgesic action of i.t. morphine was undiminished in spinally transsected animals, which indicated that the inhibition of the tail-flick response produced by i.t. morphine was on a spinal reflex response. On the other hand, spinal transsection produced a loss of the action of i.t. Dyn A to antagonize i.t. morphine-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)
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involvement of dynorphin a and not substance p in the spinal Antianalgesic action of capsaicin against morphine induced antinociception in mice
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: K S Arts, J M Fujimoto, L F TsengAbstract:In previous publications we proposed that dynorphin A (1-17) (Dyn) functions as an Antianalgesic agent in the spinal cord of mice. Whether endogenously released or administered directly to the spinal cord, this Antianalgesic action attenuates the antinociceptive effect of morphine (Mor) in the mouse tail-flick test. Because this action of Dyn in the spinal cord appeared to be congruous with the function of substance P (SP), experiments were designed to compare the actions of the two on Mor-induced antinociception. Inhibition of the tail-flick response induced by i.c.v. administration of Mor was attenuated by intrathecal (i.t.) administration of SP or Dyn. This Antianalgesic effect of Dyn (5 fmol) but not SP (74 pmol) was antagonized by naloxone and nor-binaltorphimine administered i.t. Capsaicin (Cap) i.t. at a 0.1-microgram dose, like SP and Dyn, antagonized the antinociceptive effect of Mor given i.c.v. Excellent evidence exists to indicate that, in rats, Cap (30-70 micrograms i.t.) releases SP in the spinal cord and that Mor inhibits this release. Present experiments indicated, however, that i.t. administration of low doses of Cap (0.05-0.5 microgram) in mice preferentially released Dyn and not SP as based on the following results. 1) The Antianalgesic action of Cap i.t. against Mor i.c.v. was antagonized by naloxone and nor-binaltorphimine i.t. as was Dyn i.t. (but not SP i.t.). 2) A SP antagonist, (D-Pro2, D-Phe7, D-Trp9)-SP, did not reverse the effect of Cap or Dyn given i.t., even though it antagonized the effect of SP.(ABSTRACT TRUNCATED AT 250 WORDS)
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naloxone and norbinaltorphimine administered intracerebroventricularly antagonize spinal morphine induced antinociception in mice through the Antianalgesic action of spinal dynorphin a 1 17
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: Blythe B Holmes, J M FujimotoAbstract:Previously, a number of analgesic agonists, when administered i.c.v. to mice, were shown putatively to activate the release of dynorphin A (1-17) (Dyn A) in the spinal cord. Whether released endogenously or administered i.t., Dyn A produces an Antianalgesic action against i.t. administered morphine. In the present study, the opioid antagonists, naloxone and norbinaltorphimine (N-BNI), were shown to activate the Dyn A system. Intracerebro-ventricular administration of both naloxone and N-BNI antagonized the antinociceptive effect of i.t. morphine in the mouse tail-flick test, an effect designated as an Antianalgesic action. This Antianalgesic action was demonstrated to be mediated by spinal Dyn A in the following ways: 1) the antagonistic effect of i.c.v. naloxone and N-BNI was eliminated by administration of small doses of i.t. naloxone and N-BNI, a unique situation where administration of the opioid antagonists at a second (i.t.) site reversed the antagonistic effect of opioid antagonists administered at the other (i.c.v.) site; 2) i.t. pretreatment with dynorphin antiserum prevented the Antianalgesic effect; 3) morphine pretreatment (s.c., 10 mg/kg), which produces desensitization to the effect of spinal Dyn A, eliminated the Antianalgesic effect; and 4) pretreatment with i.c.v. naloxone (3 hours) and N-BNI (24 hours) which presumably releases Dyn A produced desensitization to the antagonistic effect of i.c.v. naloxone and N-BNI as well as to the Antianalgesic action of i.t. Dyn A. Taken together, the results indicate that both i.c.v. naloxone and N-BNI produced indirect antagonistic actions which were mediated at the spinal cord by the Antianalgesic action of Dyn A.(ABSTRACT TRUNCATED AT 250 WORDS)
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Dynorphins other than dynorphin A(1-17) lack spinal Antianalgesic activity but do act on dynorphin A(1-17) receptors.
Journal of Pharmacology and Experimental Therapeutics, 1991Co-Authors: Jodie J. Rady, J M Fujimoto, L F TsengAbstract: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)
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systemic single dose morphine pretreatment desensitizes mice to the spinal Antianalgesic action of dynorphin a 1 17
Journal of Pharmacology and Experimental Therapeutics, 1990Co-Authors: J M Fujimoto, B HolmesAbstract: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.
Blythe B Holmes - One of the best experts on this subject based on the ideXlab platform.
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Inverse Agonist Action of Leu-Enkephalin at δ2-Opioid Receptors Mediates Spinal Antianalgesia
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Jodie J. Rady, Blythe B Holmes, Leon F. Tseng, James M FujimotoAbstract:Dynorphin A(1-17) given intrathecally releases spinal cholecystokinin to produce an Antianalgesic action against spinal morphine in the tail-flick test in CD-1 mice. The present study showed that following the cholecystokinin step, a δ 2 -opioid inverse agonist action of Leu-enkephalin (LE), was involved. Pretreatment with intrathecal LE antiserum eliminated dynorphin and cholecystokinin-8s antianalgesia. A small dose of LE intrathecally produced antianalgesia that like that from dynorphin A(1-17) and cholecystokinin was eliminated by naltriben but not 7-benzylidenenaltrexone (δ 2 - and δ 1 -opioid receptor antagonist, respectively). This LE step was followed by N -methyl-d-aspartate (NMDA) receptor activation. MK801, an NMDA receptor antagonist, eliminated the antianalgesia from dynorphin A(1-17), cholecystokinin-8s, and LE. Furthermore, none of the three were effective against morphine analgesia in 129S6/SvEv mice possibly because of their deficiency in NMDA receptor response. In 129S6/SvEv mice, [d-Ser 2 ]-Leu-enkephalin-Thr analgesia was not attenuated by LE; thus, this δ 2 -analgesic agonist and LE inverse agonist action did not occur through competition at the same δ 2 -receptor in CD-1 mice. In CD-1 mice, a linear sequence of dynorphin A(1-17) → cholecystokinin → LE → NMDA receptors was indicated: cholecystokinin antiserum inhibited cholecystokinin but not LE; naltriben inhibited LE but not NMDA. The uniqueness of LE in linking dynorphin A(1-17), cholecystokinin, δ 2 -opioid, and NMDA receptor activation may unify the separate known mechanisms involved in the antiopioid actions of these components against morphine.
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Antianalgesic action of dynorphin a mediated by spinal cholecystokinin
Experimental Biology and Medicine, 1999Co-Authors: Jodie J. Rady, Blythe B Holmes, James M FujimotoAbstract:: Previous work indicates that the Antianalgesic action of pentobarbital and neurotensin administered intracerebroventricularly in mice arises from activation of a descending system to release cholecystokinin (CCK) in the spinal cord where CCK is known to antagonize morphine analgesia. Spinal dynorphin, like CCK, has an Antianalgesic action against intrathecally administered morphine. This dynorphin action is indirect; even though it is initiated in the spinal cord, it requires the involvement of an ascending pathway to the brain and a descending pathway to the spinal cord where an Antianalgesic mediator works. The aim of the present investigation was to determine if the Antianalgesic action of intrathecal dynorphin A involved spinal CCK. All drugs were administered intrathecally to mice in the tail flick test. Morphine analgesia was inhibited by dynorphin as shown by a rightward shift of the morphine dose-response curve. The effect of dynorphin was eliminated by administration of the CCK receptor antagonists lorglumide and PD135 158. One hour pretreatment with CCK antiserum also eliminated the action of dynorphin. On the other hand, the Antianalgesic action of CCK was not affected by dynorphin antiserum. Thus, CCK did not release dynorphin. Both CCK and dynorphin were Antianalgesic against DSLET but not DPDPE, delta 2 and delta 1 opioid receptor peptide agonists, respectively. The results suggest that the Antianalgesic action of dynorphin occurred through an indirect mechanism ultimately dependent on the action of spinal CCK.
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Supraspinal neurotensin-induced antianalgesia in mice is mediated by spinal cholecystokinin.
Japanese Journal of Pharmacology, 1999Co-Authors: Blythe B Holmes, Jodie J. Rady, David J. Smith, James M FujimotoAbstract:Intracerebral injection of neurotensin into specific brain loci in rats produces hyperalgesia due to the release of cholecystokinin (CCK) in the spinal cord. The present purpose was to show in another species that neurotensin can antagonize the antinociceptive action of morphine through the spinal CCK mechanism in mice. Neurotensin given intracerebroventricularly (i.c.v.) at doses higher than 100 ng produced antinociception in the tail flick test. However, at lower doses between 1 pg to 25 ng, neurotensin antagonized the antinociceptive action of morphine given intrathecally (i.t.), thus demonstrating the Antianalgesic activity of neurotensin. The rightward shift in the morphine dose-response curve produced by i.c.v. neurotensin was eliminated by an i.t. pretreatment with CCK8 antibody (5 microl of antiserum solution diluted 1:1000). I.t. administration of lorglumide, a CCK(A)-receptor antagonist (10-1000 ng), and PD135,158, a CCK(B)-receptor antagonist (250-500 ng), also eliminated the Antianalgesic action of neurotensin. Thus, the mechanism of the Antianalgesic action of neurotensin given i.c.v. involved spinal CCK. This mode of action is similar to that for the Antianalgesic action of supraspinal pentobarbital which also involves spinal CCK.
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supraspinal flumazenil inhibits the Antianalgesic action of spinal dynorphin a 1 17
Pharmacology Biochemistry and Behavior, 1998Co-Authors: Jodie J. Rady, Blythe B Holmes, James M FujimotoAbstract:Abstract DynorphinA (Dyn) administered intrathecally or released spinally in mice produces antianalgesia, that is, antagonizes morphine analgesia (tail-flick test). Spinal transection eliminates this Dyn antianalgesia. Present results in mice show that intracerebroventricular administration of flumazenil, a benzodiazepine receptor antagonist, also eliminated the Antianalgesic action of Dyn; flumazenil in the brain eliminated the suppressant effect of intrathecal Dyn on intrathecal and intracerebroventricular morphine-induced antinociception. Intracerebroventricular clonidine, naloxone, and norbinaltorphimine release spinal Dyn. The latent antinociceptive actions of these compounds were uncovered by intracerebroventricular flumazenil. Thus, Dyn, given intrathecally or released spinally, activates a pathway that is inhibited by intracerebroventricular flumazenil. Dyn antianalgesia is not significantly altered by intracerebroventricular administration of bicuculline and picrotoxin, suggesting that activation of the gamma-aminobutyric acid receptor has little if any involvement in the Antianalgesic action of Dyn. The antagonistic effect of Dyn seems to be mimicked by benzodiazepine agonists. Furthermore, administration of a benzodiazepine receptor inverse agonist (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) inhibited Dyn antianalgesia as did flumazenil. Thus, flumazenil, through a benzodiazepine antagonist or inverse agonist action, interrupts, as does spinal transection, the neuronal circuit (cord/brain/cord) necessary for the Antianalgesic action of spinal Dyn. Because Dyn antianalgesia is an indirect action, activation of the neuronal circuit must lead to the release of a direct-acting Antianalgesic mediator in the spinal cord.
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Supraspinal Flumazenil Inhibits the Antianalgesic Action of Spinal Dynorphin A [1–17]
Pharmacology Biochemistry and Behavior, 1998Co-Authors: Jodie J. Rady, Blythe B Holmes, James M FujimotoAbstract:Abstract DynorphinA (Dyn) administered intrathecally or released spinally in mice produces antianalgesia, that is, antagonizes morphine analgesia (tail-flick test). Spinal transection eliminates this Dyn antianalgesia. Present results in mice show that intracerebroventricular administration of flumazenil, a benzodiazepine receptor antagonist, also eliminated the Antianalgesic action of Dyn; flumazenil in the brain eliminated the suppressant effect of intrathecal Dyn on intrathecal and intracerebroventricular morphine-induced antinociception. Intracerebroventricular clonidine, naloxone, and norbinaltorphimine release spinal Dyn. The latent antinociceptive actions of these compounds were uncovered by intracerebroventricular flumazenil. Thus, Dyn, given intrathecally or released spinally, activates a pathway that is inhibited by intracerebroventricular flumazenil. Dyn antianalgesia is not significantly altered by intracerebroventricular administration of bicuculline and picrotoxin, suggesting that activation of the gamma-aminobutyric acid receptor has little if any involvement in the Antianalgesic action of Dyn. The antagonistic effect of Dyn seems to be mimicked by benzodiazepine agonists. Furthermore, administration of a benzodiazepine receptor inverse agonist (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) inhibited Dyn antianalgesia as did flumazenil. Thus, flumazenil, through a benzodiazepine antagonist or inverse agonist action, interrupts, as does spinal transection, the neuronal circuit (cord/brain/cord) necessary for the Antianalgesic action of spinal Dyn. Because Dyn antianalgesia is an indirect action, activation of the neuronal circuit must lead to the release of a direct-acting Antianalgesic mediator in the spinal cord.
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(+)-Morphine attenuates the (−)-morphine-produced tail-flick inhibition via the sigma-1 receptor in the mouse spinal cord
Life Sciences, 2011Co-Authors: Leon F. Tseng, Quinn H Hogan, Hsiang-en WuAbstract:Abstract Aims We have previously demonstrated that pretreatment with (+)-morphine given intrathecally attenuates the intrathecal (−)-morphine-produced tail-flick inhibition. The phenomenon has been defined as antianalgesia against (−)-morphine-produced analgesia. Present experiments were then undertaken to determine if the Antianalgesic effect induced by (+)-morphine given spinally is mediated by the stimulation of the sigma-1 receptor in the mouse spinal cord. Main methods Sigma-1 receptor ligands, N -[2-(3,4-Dichlorophenyl)ethyl]- N -methyl-2-(dimethylamino)ethylamine dihydrobromide (BD1047) and (+)-pentazocine were used to determine if (+)-morphine-induced antianalgesia is mediated by the stimulation of sigma-1 receptors in the mouse spinal cord. Tail-flick test was employed to measure the nociceptive response. All compounds were given intrathecally. Key findings Pretreatment with BD1047 (1–10 μg) or (+)-pentazocine (0.1–10 μg) dose-dependently reversed the attenuation of the (−)-morphine-produced tail-flick inhibition induced by (+)-morphine (10 pg). BD1047 and (+)-pentazocine injected alone did not affect (−)-morphine-produced tail-flick inhibition. Significance The finding indicates that (+)-morphine attenuates the (−)-morphine-produced tail-flick inhibition via the activation of the sigma-1 receptors in the mouse spinal cord. Sigma-1 receptors may play an important role in opioid analgesia in the mouse spinal cord.
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(+)-Morphine attenuates the (-)-morphine-produced tail-flick inhibition via the sigma-1 receptor in the mouse spinal cord.
Life sciences, 2011Co-Authors: Leon F. Tseng, Quinn H Hogan, Hsiang-en WuAbstract:We have previously demonstrated that pretreatment with (+)-morphine given intrathecally attenuates the intrathecal (-)-morphine-produced tail-flick inhibition. The phenomenon has been defined as antianalgesia against (-)-morphine-produced analgesia. Present experiments were then undertaken to determine if the Antianalgesic effect induced by (+)-morphine given spinally is mediated by the stimulation of the sigma-1 receptor in the mouse spinal cord. Sigma-1 receptor ligands, N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide (BD1047) and (+)-pentazocine were used to determine if (+)-morphine-induced antianalgesia is mediated by the stimulation of sigma-1 receptors in the mouse spinal cord. Tail-flick test was employed to measure the nociceptive response. All compounds were given intrathecally. Pretreatment with BD1047 (1-10 μg) or (+)-pentazocine (0.1-10 μg) dose-dependently reversed the attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine (10 pg). BD1047 and (+)-pentazocine injected alone did not affect (-)-morphine-produced tail-flick inhibition. The finding indicates that (+)-morphine attenuates the (-)-morphine-produced tail-flick inhibition via the activation of the sigma-1 receptors in the mouse spinal cord. Sigma-1 receptors may play an important role in opioid analgesia in the mouse spinal cord. Copyright © 2011 Elsevier B.V. All rights reserved.
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Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse
European Journal of Pharmacology, 2007Co-Authors: Hsiang-en Wu, Jau-shyong Hong, Leon F. TsengAbstract:We have previously demonstrated that (+)-morphine and (−)-morphine given spinally stereoselectively attenuate the spinally-administered (−)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia. Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (−)-morphine also stereoselectively attenuates the systemic (−)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (−)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01–10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneously-administered (−)-morphine (5 mg/kg). Pretreatment with (−)-morphine (0.01–1.0 mg/kg) given subcutaneously also attenuates the (−)-morphine-produced tail-flick inhibition. The ED50 values for (+)-morphine and (−)-morphine for inhibiting the (−)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 μg/kg, respectively. The attenuation of the (−)-morphine-produced tail-flick inhibition induced by (+)-morphine or (−)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/kg) given subcutaneously also attenuates (−)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (−)-morphine given systemically in attenuating the systemic (−)-morphine-produced antinociception and the Antianalgesic effect of (+)-morphine and (−)-morphine is mediated by activation of the naloxone-sensitive sigma receptor.
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Stereoselective action of (+)-morphine over (-)-morphine in attenuating the (-)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse.
European journal of pharmacology, 2007Co-Authors: Hsiang-en Wu, Jau-shyong Hong, Leon F. TsengAbstract:We have previously demonstrated that (+)-morphine and (-)-morphine given spinally stereoselectively attenuate the spinally-administered (-)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia. Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (-)-morphine also stereoselectively attenuates the systemic (-)-morphine-produced tail-flick inhibition and the effects of (+)-morphine and (-)-morphine are mediated by the naloxone-sensitive sigma receptor activation in male CD-1 mice. Pretreatment with (+)-morphine at a dose of 0.01-10 ng/kg given subcutaneously dose-dependently attenuated the tail-flick inhibition produced by subcutaneously-administered (-)-morphine (5 mg/kg). Pretreatment with (-)-morphine (0.01-1.0 mg/kg) given subcutaneously also attenuates the (-)-morphine-produced tail-flick inhibition. The ED50 values for (+)-morphine and (-)-morphine for inhibiting the (-)-morphine-produced tail-flick inhibition were estimated to be 30.6 pg/kg and 97.5 microg/kg, respectively. The attenuation of the (-)-morphine-produced tail-flick inhibition induced by (+)-morphine or (-)-morphine pretreatment was reversed by the pretreatment with (+)-naloxone or by the sigma receptor antagonist BD1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) given subcutaneously. Pretreatment with (+)-pentazocine, a selective sigma receptor agonist, (1-10 mg/kg) given subcutaneously also attenuates (-)-morphine-produced tail-flick inhibition, which was restored by (+)-naloxone (4 mg/kg) or BD1047 (10 mg/kg) pretreated subcutaneously. It is concluded that (+)-morphine exhibits extremely high stereoselective action over (-)-morphine given systemically in attenuating the systemic (-)-morphine-produced antinociception and the Antianalgesic effect of (+)-morphine and (-)-morphine is mediated by activation of the naloxone-sensitive sigma receptor.
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Nonopioidergic Mechanism Mediating Morphine-Induced Antianalgesia in the Mouse Spinal Cord
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Hsiang-en Wu, James M Fujimoto, Jonathan Thompson, Randy J. Leitermann, Leon F. TsengAbstract:Intrathecal (i.t.) pretreatment with a low dose (0.3 nmol) of morphine causes an attenuation of i.t. morphine-produced analgesia; the phenomenon has been defined as morphine-induced antianalgesia. The opioid-produced analgesia was measured with the tail-flick (TF) test in male CD-1 mice. Intrathecal pretreatment with low dose (0.3 nmol) of morphine time dependently attenuated i.t. morphine-produced (3.0 nmol) TF inhibition and reached a maximal effect at 45 min. Intrathecal pretreatment with morphine (0.009–0.3 nmol) for 45 min also dose dependently attenuated morphine-produced TF inhibition. The i.t. morphine-induced antianalgesia was dose dependently blocked by the nonselective μ-opioid receptor antagonist (-)-naloxone and by its nonopioid enantiomer (+)-naloxone, but not by endomorphin-2-sensitive μ-opioid receptor antagonist 3-methoxynaltrexone. Blockade of δ-opioid receptors, κ-opioid receptors, and N -methyl-d-aspartate (NMDA) receptors by i.t. pretreatment with naltrindole, nor-binaltorphimine, and (-)-5-methyl-10,11-dihydro-5 H -dibenzo[ a , d ]cyclohepten-5,10-imine maleate (MK-801), respectively, did not affect the i.t. morphine-induced antianalgesia. Intrathecal pretreatment with antiserum against dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, β-endorphin, cholecystokinin, or substance P also did not affect the i.t. morphine-induced antianalgesia. The i.t. morphine pretreatment also attenuated the TF inhibition produced by opioid μagonist [d-Ala2, N -Me-Phe4,Gly-ol5]-enkephalin, δ-agonist deltorphin II, and κ-agonist U50,488H. It is concluded that low doses (0.009–0.3 nmol) of morphine given i.t. activate an Antianalgesic system to attenuate opioid μ-, δ-, and κ-agonist-produced analgesia. The morphine-induced antianalgesia is not mediated by the stimulation of opioid μ-, δ-, or κ-receptors or NMDA receptors. Neuropeptides such as dynorphin A(1-17), [Leu]-enkephalin, [Met]-enkephalin, β-endorphin, cholecystokinin, and substance P are not involved in this low-dose morphine-induced antianalgesia.
