Non-NMDA receptor antagonist attenuates antinociception induced by morphine but not β-endorphin, D-Pen2-D-Pen5-enkephalin, and U50, 488H administered intracerebroventricularly in mice

doi:10.1016/0143-4179(95)90084-5

Neuropeptides

Volume 28, Issue 2, February 1995, Pages 125-129

https://doi.org/10.1016/0143-4179(95)90084-5 Get rights and content

Abstract

The antinociception induced by morphine but not β-endorphin, D-Pen²-D-Pen⁵-enkephalin (DPDPE), or U50, 488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide) administered intracerebroventricularly (i.c.v.) has been previously demonstrated to be mediated by the N-Methyl-D-Aspartic Acid (NMDA) receptor. The present study was designed to determine if non-NMDA receptors are involved in opioid-induced antinociception. Antinociception was assessed by the tail-flick test in male ICR mice. Various doses of CNQX (6-Cyano-7-nitroquinoxaline-2,3-dione), a competitive non-NMDA receptor antagonist, (0.001 to 0.5 μg) injected intracerebroventricularly (i.c.v.) alone did not show any antinociceptive effect. CNQX (0.01 to 1 μg, i.c.v.) dose-dependently attenuated the inhibition of the tail-flick response induced by morphine (1 μg). However, inhibition of the tail-flick response induced by i.c.v. administered β-endorphin (1 μg), DPDPE (10 μg), or U50, 488H was not affected by i.c.v. administered CNQX. It is concluded that non-NMDA receptors are involved in i.c.v. morphine-induced antinociception. However, non-NMDA receptors are not involved in i.c.v. administered β-endorphin-, DPDPE-, and U50, 488H-induced antinociception at the supraspinal level.

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Among the opioid receptors, which have been pharmacologically classified as μ, δ, κ and ε, the existence of the ε receptor has been controversial, and this receptor is generally not recognized as a member of the opioid peptide receptor family because it has not been precisely characterized. However, results from pharmacological, physiological and opioid receptor binding studies clearly indicate the presence of ε-opioid receptors, which are distinct from μ-, δ- or κ-opioid receptors. This putative ε-opioid receptor is stimulated supraspinally by the endogenous opioid peptide β-endorphin, which induces the release of Met-enkephalin, which, in turn, acts on spinal δ2-opioid receptors to produce antinociception. In this article, this β-endorphin-sensitive ε-opioid receptor-mediated descending pain control system, which is distinct from that activated by the μ-opioid receptor agonist morphine, is described and the physiological role of the β-endorphin-mediated system in pain control activated by cold-water swimming and intraplantar injection of formalin is discussed.
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The effect of (+/−)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cyclohepten-5, 10-imine maleate (MK-801) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) injected intrathecally (i.t.) on the inhibition of the tail-flick response induced by morphine, D-Ala²-NmePhe⁴-Gly-ol-enkephalin (DAMGO), β-endorphin, D-Pen^2,5-enkephalin (DPDPE), or {(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeocetamide)} (U50, 488H) administered i.t. was studied in ICR mice. The i.t. injection of MK-801 (2 μg) or CNQX (1 μg) alone did not affect the basal tail-flick response. Morphine (0.2 μg), DAMGO (0.8 ng), β-endorphin (0.1 μg), DPDPE (0.5 μg) or U50, 488H (6 μg) caused only slight inhibition of the tail-flick response. CNQX injected i.t., but not MK-801, enhanced the inhibition of the tail-flick response induced by i.t. administered morphine, DAMGO, DPDPE or U50, 488H. However, CNQX or MK-801 injected i.t. was not effective in enhancing the inhibition of the tail-flick response induced by β-endorphin administered i.t. The potentiating effect of CNQX on tail-flick inhibition induced by morphine, DAMGO, DPDPE or U50, 488H was blocked by naloxone (from 1 to 20 μg), yohimbine (from 1 to 20 μg) or methysergide (from 1 to 20 μg) injected i.t. in a dose-dependent manner. Our results suggest that the blockade of AMPA/kainate receptors located in the spinal cord appears to be involved in enhancing the inhibition of the tail-flick response induced by stimulation of spinal μ-, δ-, and κ-opioid receptors. Furthermore, this potentiating action may be mediated by spinal noradrenergic and serotonergic receptors. However, N-methyl-D-aspartate receptors may not be involved in modulating the inhibition of the tail-flick response induced by various opioids administered spinally.
Supraspinal NMDA and non-NMDA receptors are differentially involved in the production of antinociception by morphine and β-endorphin administered itracerebroventriculary in the formalin pain model
2000, Neuropeptides
Our previous studies have demonstrated that supraspinal glutamate receptors are differentially involved in the antinociception induced by morphine and β-endorphin given intracerebroventricularly (i.c.v.) in the tail-flick and hot-plate tests. The formalin pain test was used in the present study. Injection of mice with formalin solution (2%, 10 μl) into the hindpaw intraplantarly produced the first (0–5 min) and second (20–40 min) phases of formalin responses. The formalin responses in the both phases were attenuated dose-dependently by morphine (0.125–1 μg) or β-endorphin (0.125–1 μg) administered i.c.v. 5 min before. The antinociceptive effect of morphine was slightly more potent in the second phase whereas the effect of β-endorphin was more pronounced in the first phase. MK-801 (0.1–1 μg), a non-competitive NMDA receptor antagonist, and CNQX (0.05–0.5 μg), a non-NMDA antagonist, given i.c.v., produced antinociceptive effect in the both phases, but only in a partial manner. Both MK-801 (0.05 μg) and CNQX (0.01 μg), at the dose which had no intrinsic effect, reversed the antinociceptive effect of β-endorphin (1 μg) observed during the second, but not the first, phase partially but significantly. However, the antinociceptive effect of morphine (1 μg) was not affected by the same dose of MK-801 or CNQX given i.c.v. Our results indicate that, at the supraspinal level, both NMDA and non-NMDA receptors are involved in the production of antinociception induced by supraspinally administered β-endorphin, but not morphine, in the formalin pain model.
Evidence for the existence of the β-endorphin-sensitive 'ε-opioid receptor' in the brain: The mechanisms of ε-mediated antinociception
1998, Japanese Journal of Pharmacology
Recently, μ-, δ- and κ-opioid receptors have been cloned and relatively well-characterized. In addition to three major opioid receptor types, more extensive studies have suggested the possible existence of other opioid receptor types that can be classified as non-μ, non-δ and non-κ. Based upon anatomical and binding studies in the brain, the sensitive site for an endogenous opioid peptide, β-endorphin, has been postulated to account for the unique characteristics of the opioid receptor defined as a putative ε-opioid receptor. Many ε-opioid receptors are functionally coupled to G-proteins. The functional ε-opioid receptors in the brain are stimulated by bremazocine and etorphine as well as β-endorphin, but not by selective μ-, δ- or κ-opioid receptor agonists. ε-Opioid receptor agonists injected into the brain produce profound antinociception. The brain sites most sensitive to ε-agonist-induced antinociception are located in the caudal medial medulla such as the nucleus raphe obscures, nucleus raphe pallidus and the adjacent midline reticular formation. The stimulation of ε-opioid receptors in the brain facilitates the descending enkephalinergic pathway, which probably originates from the brainstem terminating at the spinal cord. The endogenous opioid Met-enkephalin, released in the spinal cord by activation of supraspinal ε-opioid receptors, stimulates spinal δ2-opioid receptors for the production of antinociception. It is noteworthy that the ε-opioid receptor-mediated pain control system is different from that of other opioid systems. Although there appears to be no ε-selective ligand currently available, these findings provide strong evidence for the existence of the putative ε-opioid receptor and its unique function in the brain.
Antinociceptive mechanisms of Dipsacus saponin C administered intracerebroventricularly in the mouse
1996, General Pharmacology
- 1.
  1. Dipsacus saponin C (DSC) administered intracerebroventricularly (ICV) showed an antinociceptive effect in a dose-dependent (from 3.75 to 30 μg) manner as measured by the tailflick assay. The antinociception induced by DSC at the dose of 30 μg was maintained at least I h.
- 2.
  2. Sulfated cholecystokinin (CCK, from 0.1 to 0.5 ng); muscimol (a GABA_A receptor agonist, from 50 to 200 ng); MK-801 [(±)-5-methyl-10, 11-dihydro-5H-dibenzo (a,d) cyclohepten-5, 10-imine maleate, from 0.1 to 1 μg], a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist; or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione, from 0.1 to 0.5 μg), a non-NMDA receptor antagonist, injected ICV significantly reduced the inhibition of the tail-flick response induced by DSC (30 μg) administered ICV. However, naloxone (an opioid receptor antagonist, 2 μg) or baclofen (a GABA_B receptor antagonist, 10 ng) did not affect the inhibition of the tail-flick response induced by DSC.
- 3.
  3. The intrathecal (IT) injection of yohimbine (an α₂-adrenergic receptor antagonist, from 5 to 20 μg) and methysergide (a serotonin receptor antagonist, from 5 to 20 μg) but not naloxone (from 2 to 8 μg), significantly attenuated inhibition of the tail-flick response induced by DSC (30 μg) administered ICV.
- 4.
  4. Our results suggest that DSC has an antinociceptive effect when it is administered supraspinally and GABA_A, NMDA and non-NMDA receptors, but not opioid and GABA_B receptors located at the supraspinal level, may be involved in DSC-induced antinociception. Furthermore, DSC administered supraspinally may produce antinociception by stimulating descending α₂-adrenergic and serotonin pathways but not the opioidergic pathway.
Excitatory amino acid antagonists in the rostral ventromedial medulla inhibit mesencephalic morphine analgesia in rats
1996, Pain
Supraspinal opioid analgesia is mediated in part by connections between the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Morphine analgesia elicited from the PAG is respectively decreased by selective serotonergic and opioid receptor antagonists administered into the RVM, and increased by RVM neurotensin antagonists. Since glutamate and excitatory amino acid (EAA) receptors are also active in the RVM, the present study evaluated whether either competitive (AP7) or non-competitive (MK-801) N-methyl-d-aspartate (NMDA) antagonists or a kainate/AMPA (CNQX) antagonist microinjected into the RVM altered morphine (2.5 μg) analgesia elicited from the PAG as measured by the tail-flick and jump tests. Mesencephalic morphine analgesia was markedly reduced on both tests after RVM pretreatment with either AP7 (0.01-1 μg, 0.08-7.8 nmol) or MK-801 (0.03-3 μg, 0.04-4.4 nmol). In contrast, small but significant reductions in mesencephalic morphine analgesia occurred on the jump test following CNQX (0.5 μg, 2.2 nmol) in the RVM. NMDA antagonists did not markedly alter either basal nociceptive thresholds following RVM administration, or mesencephalic morphine analgesia following administration into medullary placements lateral or dorsal to the RVM. These data implicate EAA and particularly NMDA receptors in the RVM in modulating the transmission of opioid pain-inhibitory signals from the PAG.

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Non-NMDA receptor antagonist attenuates antinociception induced by morphine but not β-endorphin, D-Pen2-D-Pen5-enkephalin, and U50, 488H administered intracerebroventricularly in mice

Abstract

Neuropharmacology

Life Sci.

Life Sci.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Neuropeptides

Life Sci.

Non-NMDA receptor antagonist attenuates antinociception induced by morphine but not β-endorphin, D-Pen²-D-Pen⁵-enkephalin, and U50, 488H administered intracerebroventricularly in mice