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Antianalgesic

The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform

James M Fujimoto – 1st expert on this subject based on the ideXlab platform

  • Nonopioidergic Mechanism Mediating Morphine-Induced Antianalgesia in the Mouse Spinal Cord
    Journal of Pharmacology and Experimental Therapeutics, 2004
    Co-Authors: Hsiang-en Wu, James M Fujimoto, Jonathan Thompson, Randy J. Leitermann, Leon F. Tseng

    Abstract:

    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.

  • Nociceptin and dynorphin A(1-17) produce antianalgesia through independent systems in mice.
    Life Sciences, 2002
    Co-Authors: Jodie J. Rady, James M Fujimoto

    Abstract:

    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.

  • confluence of Antianalgesic action of diverse agents through brain interleukin1β in mice
    Journal of Pharmacology and Experimental Therapeutics, 2001
    Co-Authors: Jodie J. Rady, James M Fujimoto

    Abstract:

    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.

Jodie J. Rady – 2nd expert on this subject based on the ideXlab platform

  • Nociceptin and dynorphin A(1-17) produce antianalgesia through independent systems in mice.
    Life Sciences, 2002
    Co-Authors: Jodie J. Rady, James M Fujimoto

    Abstract:

    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.

  • confluence of Antianalgesic action of diverse agents through brain interleukin1β in mice
    Journal of Pharmacology and Experimental Therapeutics, 2001
    Co-Authors: Jodie J. Rady, James M Fujimoto

    Abstract:

    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.

  • Inverse Agonist Action of Leu-Enkephalin at δ2-Opioid Receptors Mediates Spinal Antianalgesia
    Journal of Pharmacology and Experimental Therapeutics, 2001
    Co-Authors: Jodie J. Rady, Blythe B Holmes, Leon F. Tseng, James M Fujimoto

    Abstract:

    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.

J M Fujimoto – 3rd expert on this subject based on the ideXlab platform

  • elimination of the Antianalgesic action of dynorphin a by spinal transsection in barbital anesthetized mice
    Journal of Pharmacology and Experimental Therapeutics, 1994
    Co-Authors: Fansheng Wang, J J Rady, J M Fujimoto

    Abstract:

    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)

  • 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, 1992
    Co-Authors: K S Arts, J M Fujimoto, L F Tseng

    Abstract:

    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)

  • 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, 1992
    Co-Authors: Blythe B Holmes, J M Fujimoto

    Abstract:

    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)