Analgesic effects of dynorphin-A and morphine in mice

doi:10.1016/0196-9781(85)90079-8

Peptides

Volume 6, Issue 1, 2 January 1985, Pages 75-78

https://doi.org/10.1016/0196-9781(85)90079-8 Get rights and content

Abstract

To investigate whether or not dynorphin-A is analgesic, the effect of this peptide was tested in comparison with that of morphine in mice. Dynorphin-A produced a potent analgesic effect in the acetic acid writhing and tail pinch tests, but a weak effect in the tail flick test when given by intracerebroventricular injection. In contrast, morphine caused a potent analgesia in all the tests. Dynorphin-A was more effective when given by intrathecal injection than by intracerebroventricular injection, whereas morphine was equipotent by both injection routes. The results suggest that dynorphin-A is analgesic and that its analgesia may be differentiated from that of morphine.

References (16)

H.J. Friedman et al.
Dynorphin: A possible modulatory peptide on morphine or β-endorphin analgesia in mouse
Eur J Pharmacol
(1981)
A.G. Hayes et al.
Antinociceptive profile of dynorphin in rats
Life Sci
(1983)
J.L.K. Hylden et al.
Intrathecal morphine in mice: a new technique
Eur J Pharmacol
(1980)
T. Kaneko et al.
Sites of analgesic action of dynorphin
Life Sci
(1983)
M.F. Piercey et al.
Analgesic activity of intraspinally administrated dynorphin and ethylketocyclazocine
Eur J Pharmacol
(1982)
R. Przewlocki et al.
Mixed opioid/nonopioid effects of dynorphin and dynorphin relayed peptides after their intrathecal injection in rats
Neuropeptides
(1983)
R. Przewlocki et al.
Analgesic effects of μ-, δ- and κ-opiate agonists and, in particular, dynorphin at the spinal level
Life Sci
(1983)
H. Takagi et al.
A modification of Haffner's method for testing analgesia
Jpn J Pharmacol
(1966)

There are more references available in the full text version of this article.

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Therefore, the present study was conducted to further investigate the relationship between supraspinal apelin and classical opioid receptors agonist morphine. The analgesic effect of i.c.v. morphine in our result is consistent with the previous report [25]. The APJ receptor agonist apelin-13 (0.3 μg/mouse, i.c.v.) could significantly potentiate the analgesia of 2.5 μg/kg and 5 μg/kg morphine (Fig. 4A).
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Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112
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In rodent assays investigating a variety of physiological functions, UFP-112 consistently mimicked the effects of N/OFQ with markedly higher potency and longer duration of action [6]. Given that intrathecal morphine-induced antinociception only last for 1–2 h in rodents [4,27] and the duration of antinociception can be distinguished between intrathecal morphine (4–5 h) and N/OFQ (2–3 h) in monkeys [19], it is important to examine whether the high potency and long duration of action of UFP-112 can translate to non-human primates in the absence of an itch side effect. Therefore, the aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys.
Chemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe⁴Aib⁷Arg¹⁴Lys¹⁵]N/OFQ-NH₂ (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1–10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 °C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1 mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4–5 h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia.
A Prolonged Nitric Oxide-Dependent, Opioid-Mediated Antinociceptive Effect of Hyperbaric Oxygen in Mice
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Citation Excerpt :
When mice were pretreated with a cocktail of DYN AS and β-EP AS, the HBO2-induced antinociceptive effect was reduced by two-thirds; however, this was not significantly different from the DYN AS-antagonized response to HBO2. It would appear that DYN—an opioid peptide with known antinociceptive properties18,22—is the primary mediator of HBO2-induced antinociception. Once again, this is similar to observations made in studies of N2O-induced antinociception.
Hyperbaric oxygen (HBO₂) therapy is reported to cause pain relief in several conditions of chronic pain. A single 60-minute session of HBO₂ treatment produced a prolonged antinociceptive effect in mice that persisted for 90 minutes after cessation of treatment. The HBO₂-induced antinociception was significantly attenuated by pretreatment before HBO₂ exposure with the opioid antagonist naltrexone, the nonspecific nitric oxide synthase (NOS)-inhibitor N^G-nitro-l-arginine methyl ester (L-NAME), and the selective neuronal NOS-inhibitor S-methyl-l-thiocitrulline (SMTC) but not the selective endothelial NOS-inhibitor N⁵-(1-iminoethyl)-l-ornithine (L-NIO). The antinociception was also significantly reduced by central pretreatment with a rabbit antiserum against dynorphin_1-13 but not by rabbit antisera against either β-endorphin or methionine-enkephalin. The prolonged antinociceptive effect at 90 minutes after HBO₂-induced treatment was also significantly attenuated by naltrexone but not L-NAME administered 60 minutes after HBO₂ treatment but before nociceptive testing. These findings indicate that the antinociception that persists for 90 minutes after HBO₂ exposure is mediated by nitric oxide (NO) and opioid mechanisms but that the NO involvement is critical during the HBO₂ treatment and not at the time of nociceptive testing. These results are consistent with the concept that HBO₂ may induce an NO-dependent release of opioid peptide to cause a long-acting antinociceptive effect.
This article presents evidence of a persistent antinociceptive effect of hyperbaric oxygen treatment that is mediated by opioid and NO mechanisms. Further elucidation of the underlying mechanism could identify molecular targets to cause a longer-acting activation of endogenous pain-modulating systems.
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2009, Hormones, Brain and Behavior Online
Neuropeptides synthesized in the central nervous system are potent and specific neuromodulators with the capacity to diffuse or travel to relatively distant sites within the brain. These short chains of amino acids retain potency in small concentrations – a property that permits them to entrain mass-sustained functions, such as regulation of mood, appetite, anxiety level, and libido. In addition, many neuropeptides have been pathophysiologically implicated in neuropsychiatric diseases. This chapter reviews the major neuropeptides of brain origin whose clinical relevance is established (growth hormone-releasing hormone, gonadotropin-releasing hormone, somatostatin, corticotropin-releasing hormone, thyrotropin-releasing hormone, vasopressin, oxytocin, the opioids, the melanocortins, and cholecystokinin) and a few that are of emerging or expanding clinical neuropsychiatric interest (substance P, neuropeptide Y, and orexins). Particular attention is paid to recent findings from behavioral studies, clinical physiology, and pharmacology which are furthering our understanding of the pathophysiology of numerous psychiatric and neurological disorders. An overview of the clinical approach to each neuropeptide is provided.
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The antinociceptive response of mice to the amino acid l-arginine (l-ARG) has been attributed to either an opioid mechanism or a non-opioid but nitric oxide (NO)-dependent mechanism. Earlier it was reported that the mechanism of nitrous oxide-induced antinociception involved opioid components and was also dependent on brain NO. This study was designed to determine whether the antinociceptive effects of l-ARG and the NO donor 3-morpholinosydnoimine (SIN-1) might be mediated by brain mechanisms similar to those that are responsible for nitrous oxide (N₂O) antinociception. l-ARG and SIN-1 were administered to mice intracerebroventricularly (i.c.v.), and antinociception was assessed using the acetic acid abdominal constriction test. Both l-ARG and SIN-1 caused dose-related antinociceptive effects that were blocked by naloxone and norbinaltorphimine. The antinociceptive effects of both SIN-1 and l-ARG were also blocked to a greater extent by i.c.v. administration of a rabbit antiserum against rat dynorphin 1–13 than an antiserum against methionine-enkephalin, suggesting that the SIN-1 and l-ARG effects may be related to stimulated release of dynorphin. The antinociceptive effect of l-ARG was antagonized by an inhibitor of neuoronal NO synthase enzyme, indicating that l-ARG had to be converted to NO for its antinociceptive action. These findings indicate that the mechanisms of antinociceptive action of l-ARG and SIN-1 are both mediated by dynorphin and dependent on NO.

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ArticleAnalgesic effects of dynorphin-A and morphine in mice

Abstract

Eur J Pharmacol

Life Sci

Eur J Pharmacol

Life Sci

Eur J Pharmacol

Neuropeptides

Life Sci

Jpn J Pharmacol

Article
Analgesic effects of dynorphin-A and morphine in mice