Immunomodulation of human T cell responses with receptor selective enkephalins

Mazumder, Shibnath; Nath, Indira; Dhar, Mridul

doi:10.1016/0165-2478(93)90144-q

Cited by 35 publications

(21 citation statements)

References 21 publications

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“…Preclinical studies with delta opiates have implicated their use in a wide spectrum of conditions involving analgesic (Cowan et al, 1985, Jiang et al, 1990, opiate craving (Brandt et al, 2001), tolerance and dependence (Abdelhamid et al, 1991), depression (Baamonde et al, 1992, Broom et al, 2002, diarrhea (Broccado and Improta, 1992), neuropathic and inflammatory pain (Fraser et al2000, Mika et al, 2001), potentiation of mu-opioid agonist analgesia (Porreca et al, 1992), respiration (Cheng et al,1993) immune function (Mazumder et al,1993) and Parkinson's disease (Hudzik et al, 2000). This impressive list of possible therapeutic applications has intensified the search for delta opioids.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological studies with a nonpeptidic, delta-opioid (−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((−)-NIH 11082)

Aceto

May

Harris

et al. 2007

European Journal of Pharmacology

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In the search for a selective delta-opioid receptor agonist, (-)-(1R,5R,9R)-5,9-dimethyl-2'-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((-)-NIH 11082) and the (+)-enantiomer were synthesized and tested. (-)-NIH 11082 displayed antinociceptive activity in the paraphenylquinone test (PPQ test) in male ICR mice [ED 50 = 1.9 (0.7 -5.3) mg/kg, s.c.] and showed little, if any, activity in the tail-flick and hot-plate assays. The (+)-enantiomer was essentially inactive indicating stereoselectivity. Opioid receptor subtype characterization studies indicated that naltrindole, a delta-opioid receptor antagonist, was potent versus the ED 80 of (-)-NIH 11082 in the PPQ test [AD 50 = 0.75 (0.26 -2.20) mg/kg, s.c]. beta-Funaltrexamine and norbinaltorphimine, selective mu-and kappa-receptor antagonists, respectively, were inactive versus the ED 80 of (-)-NIH 11082. In rats with inflammation-induced pain, (-)-NIH 11082 produced antihyperalgesic effects that were attenuated by naltrindole. In morphine-dependent rhesus monkeys of both sexes, (-)-NIH 11082 neither substituted for morphine nor exacerbated withdrawal signs in the dose range of 4.0 to 32.0 mg/kg, s.c. Neither convulsions nor other overt behavioral signs were observed in any of the species tested. The results indicate that (-)-NIH 11082 has delta-opioid receptor properties.

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Section: Introductionmentioning

confidence: 99%

Pharmacological studies with a nonpeptidic, delta-opioid (−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((−)-NIH 11082)

Aceto

May

Harris

et al. 2007

European Journal of Pharmacology

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“…In a parallel study, one of us [19] concluded from a review of the literature on enkephalins and immunomodulation that ‰ and Ì receptorselective compound should provide a potent immunostimulant and immunosuppressant, respectively. Accordingly, the effects on lymphocyte proliferation of the cyclic ‰ and Ì receptor-selective compounds DPDPE and TOPA were examined [10] and found to possess potent immunostimulant and immunosuppressant activity.…”

Section: Introductionmentioning

confidence: 99%

“…Although there is no unanimity, ligands of Ì-and Î-opioid receptors primarily downregulate the immune system [7,8], while ‰ and Â ligands stimulate the immune system [1,[9][10][11]. The identification of endogenous peptide ligands for these opioid receptors has provided leads for designing receptorselective, biologically stable peptide molecules.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation by Opioid Peptidomimetic Compound

Narayan¹,

Singh²,

Agarwal

et al. 2001

Neuroimmunomodulation

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Objective: As a follow-up to our earlier studies on immunomodulation with opioid peptides, we synthesized and evaluated immunomodulatory activity of four peptidomimetic compounds, i.e. Tyr-NH-C(Me)₂-CH₂-O-Phe-NH₂(1), Tyr-NH-C₆H₅-(o)-CH₂-CH₂-O-Phe-NH₂ (2), Tyr-NH-CH₂-CH₂-O-Phe-NH₂ (3) and Tyr-NH-CH(D-Et)-CH₂-O-Phe-NH₂ (4). Methods: These compounds were synthesized in solution phase and evaluated for their immunomodulatory properties in vitro by mixed lymphocyte reaction (MLR), proliferation of opioid receptor-expressing cells, production of tumor necrosis factor-α (TNF-α) and nitric oxide. Results: This study shows the immunosuppressive potential of synthetic peptidomimetic compound 3. This compound inhibited two-way MLR and suppressed the proliferation of the µ-opioid receptor expressing human embryonic kidney cells HEK 293 in vitro. Inhibition of MLR by compound 3 was reversed by naloxone (opioid receptor antagonist) and β-funaltrexamine hydrochloride (µ-opioid receptor antagonist). The immunosuppressive effect of compound 3 was further demonstrated by inhibition of TNF-α and nitric oxide production in lipopolysaccharide-stimulated human PBMCs and mouse macrophage cells RAW 264.7, respectively. Conclusion: These observations suggest that compound 3 inhibits MLR through µ-opioid receptor present on cells.

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“…Met-enkephalin has been shown to enhance human T lymphocyte proliferation in vitro induced by phytohemagglutinin, purified protein derivative and candida antigen [3,12,44]. In an earlier report, we have also shown that Met-enkephalin as well as analogs (1) and (2) stimulate T cell proliferation on the 5th day.…”

Section: Peptide Concentrationmentioning

confidence: 73%

“…Although their precise physiological significance still remains elusive, the enkephalins have been reported to exhibit analgesic, antidepressant, antianxiety and anticonvulsant activities [2]. Furthermore, enkephalins have also been found to act as immunomodulators [3][4][5][6][7][8][9][10][11][12]. Methionine-enkephalin (Met-enkephalin; Tyr-Gly-GlyPhe-Met) is produced by the cells of the neuroendocrine and immune systems which are capable of processing the pentapeptide from its precursor protein and bear its receptors on their surface.…”

Section: Introductionmentioning

confidence: 99%

δ-Opioid Receptor Antagonist Inhibits Immunomodulation by Met-Enkephalin Analogs

Singh¹,

Bajpai²,

Narayan³

et al. 1999

Neuroimmunomodulation

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The methionine-enkephalin (Met-enkephalin, Tyr-Gly- Gly-Phe-Met) analogs Tyr-D-Ala-Gly-MePhe-Met NHC₃H₇- iso (1) and Tyr-D-Ala-Gly-MePhe-Gly-NHC₃H₇-iso (2) have been shown to enhance human T cell proliferation in in vitro treatment. Their immunomodulatory activities were completely blocked by naloxone, an opioid antagonist. Now we demonstrate that a selective δ-opioid receptor antagonist, ICI-174,864, completely blocks enhancement of T cell proliferation by analogs (1) and (2). The T cell-stimulatory effect was only partially inhibited by the µ-receptor-selective antagonist, β-funaltrexamine hydrochloride. The κ-opioid receptor antagonist, nor-binaltorphimine dihydrochloride, showed no effect on T cell-proliferation stimulated by analogs (1) and (2). These observations suggest that analogs (1) and (2) of Met-enkephalin stimulate T cell proliferation predominantly via δ-opioid receptor present on T cells.

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Immunomodulation of human T cell responses with receptor selective enkephalins

Cited by 35 publications

References 21 publications

Pharmacological studies with a nonpeptidic, delta-opioid (−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((−)-NIH 11082)

Pharmacological studies with a nonpeptidic, delta-opioid (−)-(1R,5R,9R)-5,9-dimethyl-2′-hydroxy-2-(6-hydroxyhexyl)-6,7-benzomorphan hydrochloride ((−)-NIH 11082)

Immunomodulation by Opioid Peptidomimetic Compound

δ-Opioid Receptor Antagonist Inhibits Immunomodulation by Met-Enkephalin Analogs

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