Sensitivity to μ-opioid receptor-mediated anti-nociception is determined by cross-regulation between μ- and δ-opioid receptors at supraspinal level

This study investigated the mechanism of agonist-induced opioid receptor down-regulation. Incubation of HEK 293 cells expressing FLAG-tagged δ and μ receptors with agonists caused a time-dependent decrease in opioid receptor levels assayed by immunoblotting. Pulse-chase experiments using [35S]methionine metabolic labeling indicated that the turnover rate of δ receptors was accelerated 5-fold following agonist stimulation. Inactivation of functional Giand Goproteins by pertussis toxin-attenuated down-regulation of the μ opioid receptor, while down-regulation of the δ opioid receptor was unaffected. Pretreatment of cells with inhibitors of lysosomal proteases, calpain, and caspases had little effect on μ and δ opioid receptor down-regulation. In marked contrast, pretreatment with proteasome inhibitors attenuated agonist-induced μ and δ receptor down-regulation. In addition, incubation of cells with proteasome inhibitors in the absence of agonists increased steady-state μ and δ opioid receptor levels. Immunoprecipitation of μ and δ opioid receptors followed by immunoblotting with ubiquitin antibodies suggested that preincubation with proteasome inhibitors promoted accumulation of polyubiquitinated receptors. These data provide evidence that the ubiquitin/proteasome pathway plays a role in agonist-induced down-regulation and basal turnover of opioid receptors.

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Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.172918 ◽

2020 ◽

Vol 871 ◽

pp. 172918 ◽

Cited By ~ 1

Author(s):

Mohammad Zafar Imam ◽

Andy Kuo ◽

Sussan Ghassabian ◽

Yunxin Cai ◽

Yajuan Qin ◽

...

Keyword(s):

Receptor Antagonist ◽

Respiratory Depression ◽

Opioid Receptor ◽

Opioid Receptors ◽

Receptor Agonist ◽

Intracerebroventricular Administration ◽

Opioid Receptor Antagonist ◽

Opioid Receptor Agonist ◽

Μ Opioid Receptor

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Tonic GABAA receptor conductance in medial subnucleus of the tractus solitarius neurons is inhibited by activation of μ-opioid receptors

Journal of Neurophysiology ◽

10.1152/jn.00853.2011 ◽

2012 ◽

Vol 107 (3) ◽

pp. 1022-1031 ◽

Cited By ~ 11

Author(s):

Melissa A. Herman ◽

Richard A. Gillis ◽

Stefano Vicini ◽

Kenneth L. Dretchen ◽

Niaz Sahibzada

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Receptor Activation ◽

Membrane Excitability ◽

Selective Blockade ◽

Medial Nucleus ◽

Opioid Receptor Agonist ◽

Gaba Signaling ◽

Μ Opioid Receptor ◽

Μ Opioid Receptors

Our laboratory previously reported that gastric activity is controlled by a robust GABAA receptor-mediated inhibition in the medial nucleus of the tractus solitarius (mNTS) ( Herman et al. 2009 ), and that μ-opioid receptor activation inhibits gastric tone by suppression of this GABA signaling ( Herman et al. 2010 ). These data raised two questions: 1) whether any of this inhibition was due to tonic GABAA receptor-mediated conductance in the mNTS; and 2) whether μ-opioid receptor activation suppressed both tonic and phasic GABA signaling. In whole cell recordings from rat mNTS neurons, application of three GABAA receptor antagonists (gabazine, bicuculline, and picrotoxin) produced a persistent reduction in holding current and decrease in population variance or root mean square (RMS) noise, suggesting a blockade of tonic GABA signaling. Application of gabazine at a lower concentration abolished phasic currents, but had no effect on tonic currents or RMS noise. Application of the δ-subunit preferring agonist gaboxadol (THIP) produced a dose-dependent persistent increase in holding current and RMS noise. Pretreatment with tetrodotoxin prevented the action of gabazine, but had no effect on the THIP-induced current. Membrane excitability was unaffected by the selective blockade of phasic inhibition, but was increased by blockade of both phasic and tonic currents. In contrast, activation of tonic currents decreased membrane excitability. Application of the μ-opioid receptor agonist DAMGO produced a persistent reduction in holding current that was not observed following pretreatment with a GABAA receptor antagonist and was not evident in mice lacking the δ-subunit. These data suggest that mNTS neurons possess a robust tonic inhibition that is mediated by GABAA receptors containing the δ-subunit, that determines membrane excitability, and that is partially regulated by μ-opioid receptors.

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Functional coupling, desensitization and internalization of virally expressed μ opioid receptors in cultured dorsal root ganglion neurons from μ opioid receptor knockout mice

Neuroscience ◽

10.1016/j.neuroscience.2003.08.060 ◽

2004 ◽

Vol 123 (1) ◽

pp. 111-121 ◽

Cited By ~ 10

Author(s):

W.M Walwyn ◽

D.E Keith ◽

W Wei ◽

A.M Tan ◽

C.W Xie ◽

...

Keyword(s):

Dorsal Root Ganglion ◽

Opioid Receptor ◽

Opioid Receptors ◽

Knockout Mice ◽

Dorsal Root ◽

Dorsal Root Ganglion Neurons ◽

Functional Coupling ◽

Μ Opioid Receptor ◽

Ganglion Neurons ◽

Μ Opioid Receptors

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Emerging pharmacologic mechanisms of buprenorphine to explain experience of analgesia versus adverse effects

Journal of Opioid Management ◽

10.5055/jom.2021.0639 ◽

2021 ◽

Vol 17 (7) ◽

pp. 21-31

Author(s):

Jeffrey Bettinger, PharmD ◽

Himayapsill Batista Quevedo, PharmD ◽

Jacqueline Cleary, PharmD, BCACP

Keyword(s):

Adverse Effects ◽

Opioid Receptor ◽

Opioid Receptors ◽

Partial Agonist ◽

Clinical Trial Data ◽

Receptor Activation ◽

Cellular Mechanisms ◽

Μ Opioid Receptor ◽

Addictive Potential

Buprenorphine’s unique pharmacologic mechanisms of action lend itself to a higher level of complexity than its typical characterization as a partial agonist at μ-opioid receptors. It is well-documented that its additional activity at Δ- and κ-opioid receptors, and opioid receptor ligand 1 may be associated with varying degrees of analgesia and usual opioid-related adverse effects. However, novel downstream molecular and cellular mechanisms from μ-opioid receptor activation contain potential new insights into its overall unique effects. These include buprenorphine’s peculiar ability to induce analgesia at escalating doses, while exhibiting a plateaued effect on respiratory depression, euphoria, gastrointestinal (GI) motility, depression, anxiety, and addictive potential. Thus, this review aims to discuss several of these emerging mechanisms to gain a better understanding of these curious actions, as well as support much of this in vitro evidence with various human clinical trial data to further support buprenorphine’s place on the analgesic ladder.

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Involvement of μ-opioid receptors in potentiation of apomorphine-induced climbing behavior by morphine: studies using μ-opioid receptor gene knockout mice

Molecular Brain Research ◽

10.1016/s0169-328x(00)00094-2 ◽

2000 ◽

Vol 78 (1-2) ◽

pp. 204-206 ◽

Cited By ~ 11

Author(s):

Choon-Gon Jang ◽

Younjoo Park ◽

Sachiko Tanaka ◽

Tangeng Ma ◽

Horace H Loh ◽

...

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Knockout Mice ◽

Gene Knockout ◽

Receptor Gene ◽

Climbing Behavior ◽

Gene Knockout Mice ◽

Μ Opioid Receptor ◽

Μ Opioid Receptors

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Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I Na , I K(M) , and I K(erg) unlinked to interaction with opioid receptors

Drug Development Research ◽

10.1002/ddr.21568 ◽

2019 ◽

Vol 80 (6) ◽

pp. 846-856 ◽

Cited By ~ 1

Author(s):

Yuan‐Yuarn Liu ◽

Hung‐Tsung Hsiao ◽

Jeffery C.‐F. Wang ◽

Yen‐Chin Liu ◽

Sheng‐Nan Wu

Keyword(s):

Receptor Antagonist ◽

Opioid Receptor ◽

Opioid Receptors ◽

Receptor Agonist ◽

Opioid Receptor Antagonist ◽

Opioid Receptor Agonist ◽

Μ Opioid Receptor

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The μ-opioid receptor agonist morphine, but not agonists at δ- or κ-opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors

British Journal of Pharmacology ◽

10.1038/bjp.2008.175 ◽

2008 ◽

Vol 154 (5) ◽

pp. 1143-1149 ◽

Cited By ~ 53

Author(s):

D Da Fonseca Pacheco ◽

A Klein ◽

A De Castro Perez ◽

C M Da Fonseca Pacheco ◽

J N De Francischi ◽

...

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Receptor Agonist ◽

Cannabinoid Receptors ◽

Opioid Receptor Agonist ◽

Μ Opioid Receptor

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Loss of vasomotor responsiveness to the μ-opioid receptor ligand endomorphin-1 in adjuvant monoarthritic rat knee joints

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00464.2003 ◽

2004 ◽

Vol 286 (4) ◽

pp. R634-R641 ◽

Cited By ~ 19

Author(s):

Jason J. McDougall ◽

A. Kursat Barin ◽

Chelsea M. McDougall

Keyword(s):

Blood Flow ◽

Opioid Receptor ◽

Opioid Receptors ◽

Immunohistochemical Analysis ◽

Knee Joints ◽

Μ Opioid Receptor ◽

Arthritic Joints ◽

Dose Dependent Increase ◽

Dose Dependent ◽

Μ Opioid Receptors

Endomorphin-1 is a short-chain neuropeptide with a high affinity for the μ-opioid receptor and has recently been localized in acutely inflamed knee joints where it was found to reduce inflammation. The present study examined the propensity of endomorphin-1 to modulate synovial blood flow in normal and adjuvant-inflamed rat knee joints. Under deep urethane anesthesia, endomorphin-1 was topically applied to exposed normal and 1 wk adjuvant monoarthritic knee joints (0.1 ml bolus; 10-12-10-9 mol). Relative changes in articular blood flow were measured by laser Doppler perfusion imaging and vascular resistances in response to the opioid were calculated. In normal knees, endomorphin-1 caused a dose-dependent increase in synovial vascular resistance and this effect was significantly inhibited by the specific μ-opioid receptor antagonist d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr amide (CTOP) ( P < 0.0001, 2-factor ANOVA, n = 5-7). One week after adjuvant inflammation, the hypoaemic effect of endormophin-1 was completely abolished ( P < 0.0001, 2-factor ANOVA, n = 5-7). Immunohistochemical analysis of normal and adjuvant-inflamed joints showed a ninefold increase in endomorphin-1 levels in the monoarthritic knee compared with normal control. Western blotting and immunohistochemistry revealed a moderate number of μ-opioid receptors in normal knees; however, μ-opioid receptors were almost undetectable in arthritic joints. These findings demonstrate that peripheral administration of endomorphin-1 reduces knee joint blood flow and this effect is not sustainable during advanced inflammation. The loss of this hypoaemic response appears to be due to downregulation of μ-opioid receptors as a consequence of endomorphin-1 accumulation within the arthritic joint.

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