Functional role and sequence analysis of a lymphocyte orphan opioid receptor

doi:10.1016/0165-5728(95)00030-6

Journal of Neuroimmunology

Volume 59, Issues 1–2, June 1995, Pages 91-101

https://doi.org/10.1016/0165-5728(95)00030-6 Get rights and content

Abstract

Pharmacological evidence indicates that lymphocytes express opioid receptors, but this finding has been questioned. By DNA sequencing of reverse transcription-polymerase chain reaction products, we have found that mouse lymphocytes express mRNA encoding an orphan opioid receptor. These mRNA transcripts were detected in the CD4⁺, CD8⁺, and CD4⁻ CD8⁻ lymphocyte subpopulations. Northern blot analysis confirmed that splenic lymphocytes express a 1.5-kb orphan opioid receptor mRNA. Fifteen bases encoding Tyr⁷¹ -Arg⁷⁵ in the first intracellular loop are alternatively spliced, suggesting that orphan opioid receptor mRNA encodes two receptor subtypes. Treatment of lipopolysaccharide-stimulated lymphocytes with orphan opioid receptor antisense oligonucleotides suppressed polyclonal IgG and IgM production by 50%. Our results provide direct evidence that lymphocytes express an opioid-like receptor gene, and suggest that this receptor plays a functional role in immunocompetence.

References (40)

S.F. Altschul et al.
Basic local alignment search tool
J. Mol. Biol.
(1990)
J.M. Bidlack et al.
Kappaopioid binding sites on a murine lymphoma cell line
Eur. J. Pharmacol.
(1992)
J.R. Bunzow et al.
Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type
FEES Lett.
(1994)
D.J.J. Carr et al.
Enhancement of the generation of cytotoxic T cells by endogenous opiates
J. Neuroimmunol.
(1986)
D.J.J. Carr et al.
Evidence for a δ-class opioid receptor on cells of the immune system
Cell. Immunol.
(1988)
D.J.J. Carr et al.
Immunomodulatory characteristics of a novel antiproliferative protein, suppressin
J. Neuroimmunol.
(1990)
D.J.J. Carr et al.
Central α-adrenergic involvement in morphine-mediated suppression of splenic NK activity
J. Neuroimmunol.
(1994)
Y. Chen et al.
Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family
FEES Lett.
(1994)
N.E. Falke et al.
Stereospecific opiate binding in living human polymorphonuclear leukocytes
Cell biol. Int. Rep.
(1985)
K. Fukuda et al.
cDNA cloning and regional distribution of a novel member of the opioid receptor family
FEBS Lett.
(1994)

Y. Iwai et al.

Identification of sequences within the murine granulocyte-macrophage colony stimulating factor mRNA 3′ untranslated region that mediate mRNA stabilization induced by mitogen treatment of EL-4 thymoma cells

J. Biol. Chem.

(1991)

J.J. Madden et al.

Binding of naloxone to human T lymphocytes

Biochem. Pharmacol.

(1987)

J.N. Mehrishi et al.

Opiate receptors on lymphocytes and platelets in man

Clin. Immunol. Immunopathol.

(1983)

C. Mollereau et al.

ORL1, a novel member of the opioid receptor family: cloning, functional expression, and localization

FEBS Lett.

(1994)

H. Ovadia et al.

Characterization of opiate binding sites on membranes of rat lymphocytes

J. Neuroimmunol.

(1989)

T. Reisine et al.

Molecular biology of opioid receptors

Trends Neurosci.

(1993)

J.L. Bussiere et al.

Cytokine reversal of morphine-induced suppression of the antibody response

J. Pharmacol. Exp. Ther.

(1993)

D.J.J. Carr

The role of endogenous opioids and their receptors in the immune system

D.J.J. Carr et al.

Opioid receptors on cells of the immune system: evidence for δ- and κ-classes

J. Endocrinol.

(1989)

D.J.J. Carr et al.

Anti-opioid receptor antibody recognition of a binding site on brain and leukocyte opioid receptors

Neuroendocrinology

(1990)

Cited by (102)

Individual pituitary neuropeptides do not recapitulate the effects of repository corticotropin (Acthar®) on human B cells in vitro
2021, Journal of Neuroimmunology
Citation Excerpt :
Functional studies using μ- and κ-opioid receptor-specific ligands have shown relatively modest inhibitory effects on nonstimulated human B cells (Vassou et al. 2008). Expression of “nonclassical” OPRL1 has been observed in mouse splenic B cells (Halford et al. 1995) and in a human B cell line (Wick et al. 1995). OGFR expression and function have been well characterized in murine splenic B cells (Zagon et al. 2011).
Repository corticotropin injection (RCI), a complex mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides, has been found to suppress key aspects of gene expression and cellular function in human B lymphocytes in vitro. The present studies reveal that neither individual POMC peptides (α-MSH, ACTH_1-39, ACTH_1-24, β-endorphin) nor other related pituitary neuropeptides are sufficient to elicit these effects, even though specific receptors capable of transmitting signals from these peptides are expressed by human B cells. RCI's direct effects on human B cells may require complementary signals from multiple components of the preparation.
Helix-Constrained Nociceptin Peptides Are Potent Agonists and Antagonists of ORL-1 and Nociception
2015, Vitamins and Hormones
Nociceptin (orphanin FQ) is a 17-residue neuropeptide hormone with roles in both nociception and analgesia. It is an opioid-like peptide that binds to and activates the G-protein-coupled receptor opioid receptor-like-1 (ORL-1, NOP, orphanin FQ receptor, kappa-type 3 opioid receptor) on central and peripheral nervous tissue, without activating classic delta-, kappa-, or mu-opioid receptors or being inhibited by the classic opioid antagonist naloxone. The three-dimensional structure of ORL-1 was recently published, and the activation mechanism is believed to involve capture by ORL-1 of the high-affinity binding, prohelical C-terminus. This likely anchors the receptor-activating N-terminus of nociception nearby for insertion in the membrane-spanning helices of ORL-1. In search of higher agonist potency, two lysine and two aspartate residues were strategically incorporated into the receptor-binding C-terminus of the nociceptin sequence and two Lys(i) → Asp(i + 4) side chain–side chain condensations were used to generate lactam cross-links that constrained nociceptin into a highly stable α-helix in water. A cell-based assay was developed using natively expressed ORL-1 receptors on mouse neuroblastoma cells to measure phosphorylated ERK as a reporter of agonist-induced receptor activation and intracellular signaling. Agonist activity was increased up to 20-fold over native nociceptin using a combination of this helix-inducing strategy and other amino acid modifications. An NMR-derived three-dimensional solution structure is described for a potent ORL-1 agonist derived from nociceptin, along with structure–activity relationships leading to the most potent known α-helical ORL-1 agonist (EC₅₀ 40 pM, pERK, Neuro-2a cells) and antagonist (IC₅₀ 7 nM, pERK, Neuro-2a cells). These α-helix-constrained mimetics of nociceptin(1–17) had enhanced serum stability relative to unconstrained peptide analogues and nociceptin itself, were not cytotoxic, and displayed potent thermal analgesic and antianalgesic properties in rats (ED₅₀ 70 pmol, IC₅₀ 10 nmol, s.c.), suggesting promising uses in vivo for the treatment of pain and other ORL-1-mediated responses.
Endogenous Nociceptin System Involvement in Stress Responses and Anxiety Behavior
2015, Vitamins and Hormones
Citation Excerpt :
The immunological NOP receptor appears to be functionally active since N/OFQ and NOP ligands modulate proliferation of activated human and rat lymphocytes in vitro (Miller & Fulford, 2007; Peluso, Gaveriaux-Ruff, Matthes, Filliol, & Kieffer, 2001; Waits, Purcell, Fulford, & McLeod, 2004). NOP expression is implicated in the regulation of antibody production (Halford et al., 1995) and neutrophil chemotaxis (Serhan, Fierro, Chiang, & Pouliot, 2001). N/OFQ may also stimulate proinflammatory responses by triggering mast cell histamine release and increased vascular permeability in vivo (Kimura et al., 2000), although reports of inhibitory effects of N/OFQ on mast cell-mediated plasma extravasation exist (Németh et al., 1998) and we have shown that N/OFQ modulates rat splenocyte proliferation and proinflammatory cytokine production in vitro (Miller & Fulford, 2007).
The mechanisms underpinning stress-related behavior and dysfunctional events leading to the expression of neuropsychiatric disorders remain incompletely understood. Novel candidates involved in the neuromodulation of stress, mediated both peripherally and centrally, provide opportunities for improved understanding of the neurobiological basis of stress disorders and may represent targets for novel therapeutic development. This chapter provides an overview of the mechanisms by which the opioid-related peptide, nociceptin, regulates the neuroendocrine stress response and stress-related behavior. In our research, we have employed nociceptin receptor antagonists to investigate endogenous nociceptin function in tonic control over stress-induced activity of the hypothalamo-pituitary–adrenal axis. Nociceptin demonstrates a wide range of functions, including modulation of psychological and inflammatory stress responses, modulation of neurotransmitter release, immune homeostasis, in addition to anxiety and cognitive behaviors. Greater appreciation of the complexity of limbic–hypothalamic neuronal networks, together with attention toward gender differences and the roles of steroid hormones, provides an opportunity for deeper understanding of the importance of the nociceptin system in the context of the neurobiology of stress and behavior.
Nociceptin/Orphanin FQ-NOP Receptor System in Inflammatory and Immune-Mediated Diseases
2015, Vitamins and Hormones
The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the G-protein-coupled receptor NOP. Cells from the immune system express the precursor preproN/OFQ and the NOP receptor, as well as secrete N/OFQ. The activation of the N/OFQ-NOP pathway can regulate inflammatory and immune responses. Several immune activities, including leukocyte migration, cytokine and chemokine production, and lymphocytes proliferation are influenced by NOP activation. It was demonstrated that cytokines and other stimuli such as Toll-like receptor agonist (e.g., lipopolysaccharide) induce N/OFQ production by cells from innate and adaptive immune response. In this context, N/OFQ could modulate the outcome of inflammatory diseases, such as sepsis and immune-mediated pathologies by mechanisms not clearly elucidated. In fact, clinical studies revealed increased levels of N/OFQ under sepsis, arthritis, and Parkinson's disease. Preclinical and clinical studies pointed to the blockade of NOP receptor signaling as successful strategy for the treatment of inflammatory diseases. This review is focused on experimental and clinical data that suggest the participation of N/OFQ-NOP receptor activation in the modulation of the immune response, highlighting the immunomodulatory potential of NOP antagonists in the inflammatory and immunological disturbances.
Deciphering intracellular localization and physiological role of nociceptin and nocistatin
2013, Peptides
Citation Excerpt :
The distribution of N/OFQ and NOP receptors has been well described [13,39,60,81,86,106,112,113,116,117,137,169]. Outside of the CNS, N/OFQ and NOP receptors are detectable in the intestine, vas deferens, spleen and immune system [54,80,163]. Nociceptin and nocistatin are usually localized in the central nervous system (CNS) but have also been identified in the peripheral nervous system (PNS), organs and systems.
Nociceptin and nocistatin are endogenous ligands of G protein coupled receptor family. Numerous techniques have been used to study the diverse parameters including, localization, distribution and ultrastructure of these peptides. The majority of the study parameters are based on their physiological roles in different organ systems. The present study presents an overview of the different methods used for the study of nociceptin, nocistatin and their receptors. Nociceptin has been implicated in many physiological functions including, nociception, locomotion, stressed-induced analgesia, learning and memory, neurotransmitter and hormone release, renal function, neuronal differentiation, sexual and reproductive behavior, uterine contraction, feeding, anxiety, gastrointestinal motility, cardiovascular function, micturition, cough, hypoxic–ischemic brain injury, diuresis and sodium balance, temperature regulation, vestibular function, and mucosal transport. It has been noted that the use of light and electron microscopy was less frequent, though it may be one of the most promising tools to study the intracellular localization of these neuropeptides. In addition, more studies on the level of circulating nociceptin and nocistatin are also necessary for investigating their clinical roles in health and disease. A variety of modern tools including physiological, light and electron microscopy (EM) are needed to decipher the extent of intracellular localization, tissue distribution and function of these peptides. The intracellular localization of nociceptin and nocistatin will require a high resolution transmission EM capable of identifying these peptides and other supporting molecules that co-localize with them. A tracing technique could also elucidate a possible migratory ability of nociceptin and nocistatin from one cellular compartment to the other.
The effects of nociceptin peptide (N/OFQ)-receptor (NOP) system activation in the airways
2013, Peptides
Citation Excerpt :
Centrally administered N/OFQ selectively activates NOP receptors to produce bradycardia and hypotension in laboratory animals [21]. Since 1995, NOP expression has been reported in various animal and human immune cells including lymphocytes [59,115], neutrophils and monocytes [49,70,96,109,117]. Pampusch et al. reported ppN/OFQ transcript expression in porcine lymphoid tissues [93].
The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide (NOP) receptor. It is cleaved from a larger precursor identified as prepronociceptin (ppN/OFQ). NOP is a member of the seven transmembrane-spanning G-protein coupled receptor (GPCR) family. ppN/OFQ and NOP receptors are widely distributed in different human tissues. Asthma is a complex heterogeneous disease characterized by variable airflow obstruction, bronchial hyper-responsiveness and chronic airway inflammation. Limited therapeutic effectiveness of currently available asthma therapies warrants identification of new drug compounds. Evidence from animal studies suggests that N/OFQ modulates airway contraction and inflammation. Interestingly up regulation of the N/OFQ–NOP system reduces airway hyper-responsiveness. In contrast, inflammatory cells central to the inflammatory response in asthma may be both sources of N/OFQ and respond to NOP activation. Hence paradoxical dysregulation of the N/OFQ–NOP system may potentially play an important role in regulating airway inflammation and airway tone. To date there is no data on N/OFQ–NOP expression in the human airways. Therefore, the potential role of N/OFQ–NOP system in asthma is unknown. This review focuses on its physiological effects within airways and potential value as a novel asthma therapy.

View all citing articles on Scopus

^☆: This work does not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred.

View full text

Research paperFunctional role and sequence analysis of a lymphocyte orphan opioid receptor☆

Abstract

J. Mol. Biol.

Eur. J. Pharmacol.

FEES Lett.

J. Neuroimmunol.

Cell. Immunol.

J. Neuroimmunol.

J. Neuroimmunol.

FEES Lett.

Cell biol. Int. Rep.

FEBS Lett.

J. Biol. Chem.

Biochem. Pharmacol.

Clin. Immunol. Immunopathol.

FEBS Lett.

J. Neuroimmunol.

Trends Neurosci.

Cytokine reversal of morphine-induced suppression of the antibody response

J. Pharmacol. Exp. Ther.

The role of endogenous opioids and their receptors in the immune system

Opioid receptors on cells of the immune system: evidence for δ- and κ-classes

J. Endocrinol.

Anti-opioid receptor antibody recognition of a binding site on brain and leukocyte opioid receptors

Neuroendocrinology

Research paper
Functional role and sequence analysis of a lymphocyte orphan opioid receptor☆