Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by α2-adrenoceptors

doi:10.1016/0014-2999(95)00823-3

European Journal of Pharmacology

Volume 298, Issue 3, 18 March 1996, Pages 235-239

https://doi.org/10.1016/0014-2999(95)00823-3 Get rights and content

Abstract

Spinal administration of morphine or [d-Ala²,MePhe⁴,Gly(ol)⁵)]enkephalin (DAMGO) produces potent, naloxone-reversible analgesia that is modulated by α₂-adrenoceptors. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH₂) is a naturally occurring, amidated tetrapeptide that is structurally related to the melanocyte-stimulating hormone release inhibiting factor-1 (MIF-1) family of endogenous peptides. Tyr-W-MIF-1 displays high selectivity for the μ-opioid receptor. We investigated the effect of spinal administration of Tyr-W-MIF-1 on analgesia using the mouse tail-flick assay. Intrathecal (i.t.) administration of Tyr-W-MIF-1 produced a dose-dependent analgesic response, with an ED₅₀ of 0.41 μg, that was reversed by naloxone. Pretreatment with the μ-opioid receptor-selective antagonist β-funaltrexamine blocked the effect of i.t. Tyr-W-MIF-1. However, pretreatment with the μ₁-opioid receptor-selective antagonist naloxonazine did not antagonize the analgesia, indicating the effect was mediated through spinal μ₂-opioid receptors. Pretreatment with desipramine, an inhibitor of norepinephrine reuptake, potentiated the analgesic effect of i.t. Tyr-W-MIF-1, producing a 3.1-fold leftward shift in the dose-response curve. Spinal administration of yohimbine, an α₂-adrenoceptor-selective antagonist, significantly attenuated the analgesic effect of Tyr-W-MIF-1. Thus, the potent analgesic effect of i.t. Tyr-W-MIF-1 is mediated through spinal μ₂-receptors, and is modulated by norepinephrine and α₂-adrenoceptors.

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Cited by (19)

Noradrenaline induces peripheral antinociception by endogenous opioid release
2018, Pharmacological Reports
Citation Excerpt :
The administration of the aminopeptidase inhibitor bestatin prior to the administration of a low dose of NA (20 ng) intensified NA-induced antinociception against PGE2 (Fig. 3). Interactions between the adrenergic and opioid systems to produce antinociception have been reported in the central [13–16] and peripheral nervous systems [6,17]. Generally, NA is associated with peripheral nociceptive effects [5], but recently, it has been shown to contribute to peripheral antinociception [6,10].
The aim of this study was to investigate this involvement in not inflammatory model of pain and which opioid receptor subtype mediates noradrenaline-induced peripheral antinociception. Noradrenaline is involved in the intrinsic control of pain-inducing pro-nociceptive effects in the primary afferent nociceptors. However, inflammation can induce various plastic changes in the central and peripheral noradrenergic system that, upon interaction with the immune system, may contribute, in part, to peripheral antinociception.
Hyperalgesia was induced by intraplantar injection of prostaglandin E₂ (PGE₂, 2 μg) into the plantar surface of the right hind paw and the paw pressure test to evaluated the hyperalgesia was used. Noradrenaline (NA) was administered locally into right hind paw of Wistar rat (160–200 g) alone and after either agents, α₂-adrenoceptor antagonist yohimbine, α₁-adrenoceptor antagonist prazosin, β-adrenoceptor antagonist propranolol, μ-opioid antagonist clocinnamox, δ-opioid antagonist naltrindole and κ-opioid antagonist nor-binaltorfimina. In addition, the enkephalinase inhibitor bestatin was administered prior to NA low dose.
Intraplantar injection of NA induced peripheral antinociception against hyperalgesia induced by PGE₂. This effect was reversed, in dose dependent manner, by intraplantar injection of yohimbine, prazosin, propranolol, clocinnamox and naltrindole. However, injection of nor-binaltorfimina did not alter antinociception of NA after PGE₂ hyperalgesia. Bestatin intensified the antinociceptive effects of low-dose of NA.
Besides the α₂-adrenoceptor, the present data provide evidence that, in absence of inflammation, NA activating α₁ and β-adrenoceptor induce endogenous opioid release to produce peripheral antinociceptive effect by μ and δ opioid receptors.
A selective fluorescence reaction for peptides and chromatographic analysis
2008, Peptides
A novel and selective fluorescence reaction is proposed for the quantitative determination of peptides by reversed-phase liquid chromatography (RPLC). A single fluorescent product was formed when a peptide was heated at 120 °C for 20 min in a neutral aqueous medium (pH 7.0) containing catechol, sodium periodate, and sodium borate. The fluorescent products of four peptides such as Leu-Gly, Ala-Leu-Gly, Tyr-Gly-Gly-Phe-Leu, and Leu-Leu-Leu were easily separated on a reversed-phase column by gradient elution of methanol in a mobile phase containing sodium borate (pH 7.0), and then quantitatively detected by fluorimetry. The lower limits (S/N = 3) of the detection for the tested peptides were 0.5–1.0 pmol per an injection volume (40 μl). In addition, the fluorescent products of phenylalanine amide and Leu-Leu-Leu were identified by electrospray ionization-time of flight-mass spectrometry (ESI-TOF/MS) for the elucidation of their chemical structures.
From MIF-1 to endomorphin: The Tyr-MIF-1 family of peptides
2007, Peptides
The Tyr-MIF-1 family of small peptides has served a prototypic role in the introduction of several novel concepts into the peptide field of research. MIF-1 (Pro-Leu-Gly-NH₂) was the first hypothalamic peptide shown to act “up” on the brain, not just “down” on the pituitary. In several situations, including clinical depression, MIF-1 exhibits an inverted U-shaped dose–response relationship in which increasing doses can result in decreasing effects. This tripeptide also can antagonize opiate actions, and the first report of such activity also correctly predicted the discovery of other endogenous antiopiate peptides. The tetrapeptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH₂) not only shows antiopiate activity, but also considerable selectivity for the mu-opiate binding site. Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH₂) is an even more selective ligand for the mu receptor, leading to the discovery of two more Tyr-Pro tetrapeptides that have the highest specificity and affinity for this site. These are the endomorphins: endomorphin-1 is Tyr-Pro-Trp-Phe-NH₂ and endomorphin-2 is Tyr-Pro-Phe-Phe-NH₂. Tyr-MIF-1 proved, contrary to the then prevailing dogma, that peptides can be saturably transported across the blood–brain barrier by a quantifiable transport system. Unexpectedly, the Tyr-MIF-1 transporter is shared with Met-enkephalin. In the era in which it was doubtful whether a peripheral peptide could exert CNS effects, the Tyr-MIF-1 family of peptides also explicitly showed that they can exert more than one central action that persists longer than their half-lives in blood. These peptides clearly illustrate that the name of a peptide restricts neither its actions nor its conceptual implications.
A Tyr-W-MIF-1 analog containing d-Pro<sup>2</sup> discriminates among antinociception in mice mediated by different classes of μ-opioid receptors
2007, European Journal of Pharmacology
The antagonism by Tyr-d-Pro-Trp-Gly-NH₂ (d-Pro²-Tyr-W-MIF-1), a Tyr-Pro-Trp-Gly-NH₂ (Tyr-W-MIF-1) analog, of the antinociception induced by the μ-opioid receptor agonists Tyr-W-MIF-1, [d-Ala²,NMePhe⁴,Gly(ol)⁵]-enkephalin (DAMGO), Tyr-Pro-Trp-Phe-NH₂ (endomorphin-1), and Tyr-Pro-Phe-Phe-NH₂ (endomorphin-2) was studied with the mouse tail-flick test. d-Pro²-Tyr-W-MIF-1 (0.5–3 nmol) given intracerebroventricularly (i.c.v.) had no effect on the thermal nociceptive threshold. High doses of d-Pro²-Tyr-W-MIF-1 (4–16 nmol) administered i.c.v. produced antinociception with a low intrinsic activity of about 30% of the maximal possible effect. d-Pro²-Tyr-W-MIF-1 (0.25–2 nmol) co-administered i.c.v. showed a dose-dependent attenuation of the antinociception induced by Tyr-W-MIF-1 or DAMGO without affecting endomorphin-2-induced antinociception. A 0.5 nmol dose of d-Pro²-Tyr-W-MIF-1 significantly attenuated Tyr-W-MIF-1-induced antinociception but not DAMGO- or endomorphin-1-induced antinociception. The highest dose (2 nmol) of d-Pro²-Tyr-W-MIF-1 almost completely attenuated Tyr-W-MIF-1-induced antinociception. However, that dose of d-Pro²-Tyr-W-MIF-1 significantly but not completely attenuated endomorphin-1 or DAMGO-induced antinociception, whereas the antinociception induced by endomorphin-2 was still not affected by d-Pro²-Tyr-W-MIF-1. Pretreatment i.c.v. with various doses of naloxonazine, a μ₁-opioid receptor antagonist, attenuated the antinociception induced by Tyr-W-MIF-1, endomorphin-1, endomorphin-2, or DAMGO. Judging from the ID₅₀ values for naloxonazine against the antinociception induced by the μ-opioid receptor agonists, the antinociceptive effect of Tyr-W-MIF-1 is extremely less sensitive to naloxonazine than that of endomorphin-1 or DAMGO. In contrast, endomorphin-2-induced antinociception is extremely sensitive to naloxonazine. The present results clearly suggest that d-Pro²-Tyr-W-MIF-1 is a selective antagonist for the μ₂-opioid receptor in the mouse brain. d-Pro²-Tyr-W-MIF-1 may also discriminate between Tyr-W-MIF-1-induced antinociception and the antinociception induced by endomorphin-1 or DAMGO, which both show a preference for the μ₂-opioid receptor in the brain.
Intrathecal endomorphin-1 produces antinociceptive activities modulated by alpha 2-adrenoceptors in the rat tail flick, tail pressure and formalin tests
2000, Life Sciences
It is known that spinal morphine produces antinociception that is modulated by alpha 2-adrenoceptors. Endomorphin-1, a newly-isolated endogenous opioid ligand, shows the greatest selectivity and affinity for the mu-opiate receptor of any endogenous substance found to date and may serve as a natural ligand for the mu-opiate receptor. We examined the antinociceptive effects of endomorphin-1 administered intrathecally (i.t.) in the rat tail flick, tail pressure and formalin tests. Intrathecal endomorphin-1 produced dose-dependent antinociceptive effects in the three tests ED₅₀ (CI₉₅) values for antinociception of i.t. endomorphin-1 in the tail flick test and tail pressure test were 1.9 (0.96–3.76) nmol and 1.8 (0.8–4.2) nmol, respectively ED₅₀. (CI₉₅) values for phase 1 and phase 2 in the formalin test were 12.5 (7.9–19.8) nmol and 17.5 (10.2–30) nmol, respectively. Pretreatment with i.t. Beta-funaltrexamine (a mu-opioid receptor selective antagonist) significantly antagonized the antinociceptive effects of endomorphin-1 in the three tests. Beta-funaltrexamine alone had not effects on the three tests. The antinociceptive effects of endomorphin-1 were also antagonized by i.t. yohimbine (an alpha 2-adrenoceptor selective antagonist). The combination of ineffective doses of i.t. clonidine (an alpha 2-adrenoceptor agonist) and endomorphin-1 produced a significant antinociception in the three tests. The results showed that intrathecal endomorphin-1 produced antinociception in a dose-dependent manner in the rat tail flick, tail pressure and formalin tests, which was mediated by spinal mu-opioid receptors and modulated by alpha 2-adrenoceptors.
Cross-tolerance between analgesia produced by xylazine and selective opioid receptor subtype treatments
2000, European Journal of Pharmacology
Opioid receptor agonists produce analgesia through multiple systems activated by stimulation of μ₁, μ₂, δ₁, δ₂ and κ₁ opioid receptors. Morphine analgesia is modulated by stimulation of α₂ adrenoceptors. To understand how multiple opioid analgesic systems interact with α₂-adrenoceptor systems, analgesic cross-tolerance between the α₂ adrenoceptor agonist xylazine and opioid receptor agonists was studied using the mouse tail-flick assay. Mice received either xylazine (20 mg/kg, s.c.) or saline (1 ml/kg) for five days. On day six, mice received a dose of s.c. xylazine, i.c.v. [d-Ala²,MePhe⁴,Gly(ol)⁵]enkephalin (DAMGO), i.t. Tyr-Pro-Trp-Gly-NH₂ (Tyr-W-MIF-1), i.c.v. or i.t. [d-Pen²,d-Pen⁵]enkephalin (DPDPE), i.t. [d-Ala²]deltorphin II (deltorphin II), or s.c. trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl-cyclohexyl] benzeneacetamide (U50,488). Xylazine tolerant mice required 4.57-fold more xylazine to elicit the same response as saline treated animals and showed a 2.55-fold shift in i.c.v. DAMGO and a 3.37-fold shift in i.c.v. DPDPE antinociception. No cross-tolerance was seen with i.c.v. deltorphin II, i.t.Tyr-W-MIF-1, i.t. DPDPE, i.t. Tyr-W-MIF-1 or s.c. U50,488. These results implicate α₂ adrenoceptor systems in the modulation of supraspinal μ₁, and δ₁ opioid analgesic circuitry and raise the possibility that μ₂, δ₂ or κ₁ opioid receptor agonists may be alternated with α₂ adrenoceptor agonists to minimize tolerance or treat opioid-tolerant patients.

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Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by α2-adrenoceptors

Abstract

Brain Res.

Peptides

Peptides

Neuropeptides

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Neurosci. Lett.

Peptides

Intrathecal Tyr-W-MIF-1 produces potent, naloxone-reversible analgesia modulated by α₂-adrenoceptors