Dynorphin, a preferential ligand for κ-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat

doi:10.1016/0304-3940(92)90688-4

Neuroscience Letters

Volume 140, Issue 1, 8 June 1992, Pages 85-88

https://doi.org/10.1016/0304-3940(92)90688-4 Get rights and content

Abstract

Exogenous κ-opioid agonists have been shown to produce peripheral antinociceptive effects in inflamed tissue. This study sought to determine whether endogenous κ-receptor ligands are present at the site of inflammation. In Freund's adjuvant-induced hindpaw inflammation in the rat, we show, by immunohistochemistry, that dynorphin is detectable within inflammatory cells and in the cutaneous nerves in a similar distribution as calcitonin gene-related peptide, a specific marker for sensory neurons. These findings extend our previous observations in that not only β-endorphin and Met-enkephalin (μ- and δ-receptor ligands), but also a preferential κ-ligand is present within inflamed subcutaneous tissue.

References (27)

L.A. Chahl et al.
Plasma extravasation induced by dynorphin-(1–13) in rat skin
Eur. J. Pharmacol.
(1986)
J. Haley et al.
Peripheral κ-opioid modulation of the formalin response: an electrophysiological study in the rat
Eur. J. Pharmacol.
(1990)
A.H.S. Hassan et al.
Immunocytochemical demonstration of opioid receptors in selected rat brain areas and neuroblastoma × glioma hybrid (NG108-15) cells using a monoclonal anti-idiotypic antibody
Neuroscience
(1989)
Y. Kuraishi et al.
Calcitonin gene-related peptide increases in the dorsal root ganglia of adjuvant arthritic rat
Peptides
(1989)
S.C. Landis et al.
Coexistence of calcitonin gene-related peptide and vasoactive intestinal peptide in cholinergic sympathetic innervation of rat sweat glands
Brain Res.
(1986)
N.J.W. Russell et al.
Opiates inhibit the discharges of fine afferent units from inflamed knee joint of the cat
Neurosci. Lett.
(1987)
C. Stein et al.
Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds
Pharmacol. Biochem. Behav.
(1988)
C. Stein et al.
Antinociceptive effects of μ- and κ-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism
Eur. J. Pharmacol.
(1988)
K. Sugiyama et al.
Histamine release induced by dynorphin-(1–13) from rat mast cells
Jpn. J. Pharmacol.
(1984)
E. Weihe et al.
Immunohistochemical evidence for a co-transmitter role of opioid peptides in primary sensory neurons
Prog. Brain Res.
(1988)

M. Zimmermann

Ethical guidelines for investigations of experimental pain in conscious animals

Pain

(1983)

L. Barthó et al.

Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation

Naunyn Schmiedeberg's Arch. Pharmacol.

(1990)

H.M. Chang et al.

Sufentanil, Morphine, Met-enkephalin, and κ-agonist (U-50, 488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions

Anesthesiology

(1989)

Cited by (81)

Immune cell-mediated opioid analgesia
2020, Immunology Letters
Citation Excerpt :
Met-ENK was additionally found in proinflammatory, colitogenic Th1 and Th17 lymphocytes in inflamed colon and draining lymph nodes in the chronic colitis [119–121]. DYN was identified in blood and lymph node lymphocytes, and in granulocytes and mononuclear cells in inflamed paws [104,118,122] in the CFA-induced inflammation. The mRNAs of POMC, PENK and PDYN, as well as END and DYN were measured in peritoneal cells comprising neutrophils and monocytes/macrophages in zymosan- or thioglycollate-induced peritoneal inflammation [123,124].
Pathological pain is regulated by a balance between pro-algesic and analgesic mechanisms. Interactions between opioid peptide-producing immune cells and peripheral sensory neurons expressing opioid receptors represent a powerful intrinsic pain control in animal models and in humans. Therefore, treatments based on general suppression of immune responses have been mostly unsuccessful. It is highly desirable to develop strategies that specifically promote neuro-immune communication mediated by opioids. Promising examples include vaccination-based recruitment of opioid-containing leukocytes to painful tissue and the local reprogramming of pro-algesic immune cells into analgesic cells producing and secreting high amounts of opioid peptides. Such approaches have the potential to inhibit pain at its origin and be devoid of central and systemic side effects of classical analgesics. In support of these concepts, in this article, we describe the functioning of peripheral opioid receptors, migration of opioid-producing immune cells to inflamed tissue, opioid peptide release, and the consequent pain relief. Conclusively, we provide clinical evidence and discuss therapeutic opportunities and challenges associated with immune cell-mediated peripheral opioid analgesia.
The efficacy of Dynorphin fragments at the κ, μ and δ opioid receptor in transfected HEK cells and in an animal model of unilateral peripheral inflammation
2017, Peptides
Citation Excerpt :
Dynorphins are a series of peptides that bind to the κ-opioid receptor (KOP) and mediate anti-nociception peripherally [1,2]. In the periphery, leukocytes have been shown to invade sites of inflammation and release opioid peptides including dynorphin A 1–17, in response to pro-inflammatory interleukin-1β and lipopolysaccharide [3–5]. The opioid receptors μ-opioid receptor (MOP), δ-opioid receptor (DOP) and KOP mediate analgesia both peripherally and centrally and the release of endogenous opioids at the peripheral site of inflammation acts as an endogenous analgesic [6].
Dynorphin 1–17 is an endogenous peptide that is released at sites of inflammation by leukocytes, binding preferentially to κ-opioid receptors (KOP) to mediate nociception. We have previously shown that dynorphin 1–17 is rapidly biotransformed to smaller peptide fragments in inflamed tissue homogenate. This study aimed to determine the efficacy and potency of selected dynorphin fragments produced in an inflamed environment at the KOP, μ and δ-opioid receptors (MOP and DOP respectively) and in a model of inflammatory pain. Functional activity of Dynorphin 1–17 and fragments (1–6, 1–7 and 1–9) were screened over a range of concentrations against forskolin stimulated human embryonic kidney 293 (HEK) cells stably transfected with one of KOP, MOP or DOP. The analgesic activity of dynorphin 1–7 in a unilateral model of inflammatory pain was subsequently tested. Rats received unilateral intraplantar injections of Freund’s Complete Adjuvant to induce inflammation. After six days rats received either dynorphin 1–7, 1–17 or the selective KOP agonist U50488H and mechanical allodynia determined. Dynorphin 1–7 and 1–9 displayed the greatest activity across all receptor subtypes, while dynorphin 1–7, 1–9 and 1–17 displaying a potent activation of both KOP and DOP evidenced by cAMP inihibition. Administration of dynorphin 1–7 and U50488H, but not dynorphin 1–17 resulted in a significant increase in paw pressure threshold at an equimolar dose suggesting the small peptide dynorphin 1–7 mediates analgesia. These results show that dynorphin fragments produced in an inflamed tissue homogenate have changed activity at the opioid receptors and that dynorphin 1–7 mediates analgesia.
Leukocyte opioid receptors mediate analgesia via Ca<sup>2+</sup>-regulated release of opioid peptides
2016, Brain, Behavior, and Immunity
Citation Excerpt :
In contrast, the injection of opioid peptide antibodies to tissue devoid of leukocytes (i.e., paws innervated by damaged nerves) did not alter exogenous opioid analgesia. This finding also indicates that endogenous opioids from other sources, for example, peripheral nerves and keratinocytes (Carlton and Coggeshall, 1997; Fell et al., 2014; Hassan et al., 1992; Obara et al., 2009), are not involved. Our experiments with the transfer of immune cells lacking DOR, MOR or KOR clearly show that leukocyte opioid receptors are required for the full manifestation of exogenous opioid analgesia in vivo.
Opioids are the most powerful analgesics. As pain is driven by sensory transmission and opioid receptors couple to inhibitory G proteins, according to the classical concept, opioids alleviate pain by activating receptors on neurons and blocking the release of excitatory mediators (e.g., substance P). Here we show that analgesia can be mediated by opioid receptors in immune cells. We propose that activation of leukocyte opioid receptors leads to the secretion of opioid peptides Met-enkephalin, β-endorphin and dynorphin A (1–17), which subsequently act at local neuronal receptors, to relieve pain. In a mouse model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve, exogenous agonists of δ-, μ- and κ-opioid receptors injected at the damaged nerve infiltrated by opioid peptide- and receptor-expressing leukocytes, produced analgesia, as assessed with von Frey filaments. The analgesia was attenuated by pharmacological or genetic inactivation of opioid peptides, and by leukocyte depletion. This decrease in analgesia was restored by the transfer of wild-type, but not opioid receptor-lacking leukocytes. Ex vivo, exogenous opioids triggered secretion of opioid peptides from wild-type immune cells isolated from damaged nerves, which was diminished by blockade of Gαi/o or Gβγ (but not Gαs) proteins, by chelator of intracellular (but not extracellular) Ca²⁺, by blockers of phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP₃) receptors, and was partially attenuated by protein kinase C inhibitor. Similarly, the leukocyte depletion-induced decrease in exogenous opioid analgesia was re-established by transfer of immune cells ex vivo pretreated with extracellular Ca²⁺ chelator, but was unaltered by leukocytes pretreated with intracellular Ca²⁺ chelator or blockers of Gαi/o and Gβγ proteins. Thus, both ex vivo opioid peptide release and in vivo analgesia were mediated by leukocyte opioid receptors coupled to the Gαi/o–Gβγ protein–PLC–IP₃ receptors–intracellular Ca²⁺ pathway. Our findings suggest that opioid receptors in immune cells are important targets for the control of pathological pain.
Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the κ-opioid receptor
2008, Journal of Neuroimmunology
Citation Excerpt :
While current evidence suggests that dynorphin expression is constitutive in the nervous system, there is evidence that preprodynorphin mRNA expression is inducible through cAMP responsive elements in the preprodynorphin promoter (Messersmith et al., 1994). Furthermore, there is evidence that inflammatory responses in the periphery are accompanied by an accumulation of dynorphin A at both the inflammatory site and in the spinal cord (Hassan et al., 1992; Ruda et al., 1988), and interleukin 1 induces the production of dynorphin A at sites of inflammation (Schafer et al., 1994). Neuroinflammatory conditions would create an environment in which elevated dynorphin would be capable of exerting greater cross-desensitization of CXCR4, potentially disrupting normal neuronal development.
We previously characterized multiple interactions between chemokine and opioid G protein-coupled receptors (GPCR), and we found both μ and δ-opioid receptors cross-desensitize CCR1, CCR2, CCR5, but not CXCR4. Here we report that the κ-opioid receptor (KOR) is able to cross-desensitize CXCR4, and this phenomenon is bi-directional. Chemotactic responses by KOR activation are diminished with prior activation of CXCR4. Additionally, calcium mobilization assays show these cross-desensitization processes occur within seconds of receptor activation, and target receptor internalization is not responsible for desensitization between these receptors. These results have implications for several essential processes including neuronal and lymphocyte development, inflammatory responses, and pain/sensitivity.
Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis
2008, Brain, Behavior, and Immunity
There exists a bidirectional regulatory circuit between the nervous and immune systems. This regulation has been shown to be mediated in part through neuroendocrine hormones and cytokines. Both systems have receptors for both types of signal molecules. The nervous system has receptors for cytokines and it also synthesizes cytokines. The immune system synthesizes and responds to cytokines. So, it is not too farfetched to believe that neuroendocrine peptide hormones could bind to leukocytes and modulate immune functions. However, it is not widely known that the immune system also synthesizes functional, neuropeptide hormones. This will be discussed in this paper citing a plethora of evidence. The aim of this paper is to summarize this evidence by using three neuropeptides that are synthesized by leukocytes and modulate immune functions as examples; corticotropin (ACTH), endorphin (END), and corticotropin releasing factor (CRF). The production and action of these three neuropeptides in the immune system will be explained. Finally, the potential physiological role of leukocyte-derived ACTH, END, and CRF in inflammation as a localized hypothalamic–pituitary-like axis is discussed.
The expression of prodynorphin gene is down-regulated by activation with lipopolysaccharide in U-937 macrophage cells
2006, Journal of Neuroimmunology
Dynorphins are endogenous kappa opioid peptides widely distributed in the central nervous system. A number of recent reports have established their roles in modulating immunological functions. In this study, we investigated the expression of prodynorphin (PDYN) gene, which encodes the precursor of dynorphin peptides, in human macrophage U-937 cell line. PDYN mRNA was expressed at a detectable level, measured with a standard RT-PCR method in U-937 cells, but not in Jurkat and Raji cells, which are human T and B lymphocytes, respectively. Further analyses with RT-PCR assays by using primers covering each exon of the PDYN gene showed that U-937 cells expressed the adult brain-type PDYN mRNA. Most interestingly, activation of U-937 cells with lipopolysaccharide (LPS) led to a decrease in PDYN mRNA levels. This decrease was dependent on both the concentration of LPS and the duration of LPS treatment. In order to test the role of transcription in LPS-mediated down-regulation of PDYN gene expression in U937 cells, the proximal PDYN gene promoter with a length of either ∼300 base pairs or ∼900 base pairs was cloned and inserted upstream of luciferase reporter gene. Results from transient transfections and dual luciferase assays showed that PDYN gene promoter activity was decreased by LPS treatment. Taken together, our results suggested the U-937 cells expressed adult brain-type PDYN mRNA which was down-regulated by activation of the cells with LPS due to an inhibition of PDYN gene transcription.

View all citing articles on Scopus

View full text

Dynorphin, a preferential ligand for κ-opioid receptors, is present in nerve fibers and immune cells within inflamed tissue of the rat

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuroscience

Peptides

Brain Res.

Neurosci. Lett.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Jpn. J. Pharmacol.

Prog. Brain Res.

Pain

Involvement of capsaicin-sensitive neurones in hyperalgesia and enhanced opioid antinociception in inflammation

Naunyn Schmiedeberg's Arch. Pharmacol.

Sufentanil, Morphine, Met-enkephalin, and κ-agonist (U-50, 488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions

Anesthesiology