μ Opioid Receptor Activation Inhibits GABAergic Inputs to Basolateral Amygdala Neurons Through Kv1.1/1.2 Channels

2006 ◽  
Vol 95 (4) ◽  
pp. 2032-2041 ◽  
Author(s):  
Thomas F. Finnegan ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Basolateral Amygdala ◽  
Receptor Activation ◽  
Peak Amplitude ◽  
Amygdaloid Nucleus ◽  
Synaptic Inputs ◽  
Μ Opioid Receptor ◽  
Immunofluorescence Labeling ◽  
Μ Opioid Receptors

The basolateral amygdala (BLA) is the major amygdaloid nucleus distributed with μ opioid receptors. The afferent input from the BLA to the central nucleus of the amygdala (CeA) is considered important for opioid analgesia. However, little is known about the effect of μ opioids on synaptic transmission in the BLA. In this study, we examined the effect of μ opioid receptor stimulation on the inhibitory and excitatory synaptic inputs to CeA-projecting BLA neurons. BLA neurons were retrogradely labeled with a fluorescent tracer injected into the CeA of rats. Whole cell voltage-clamp recordings were performed on labeled BLA neurons in brain slices. The specific μ opioid receptor agonist, (d-Ala2, N-Me-Phe4,Gly5-ol)-enkephalin (DAMGO, 1 μM), significantly reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in 77% of cells tested. DAMGO also significantly decreased the peak amplitude of evoked IPSCs in 75% of cells examined. However, DAMGO did not significantly alter the frequency of mEPSCs or the peak amplitude of evoked EPSCs in 90% and 75% of labeled cells, respectively. Bath application of the Kv channel blockers, 4-AP (Kv1.1, 1.2, 1.3, 1.5, 1.6, 3.1, 3.2), α-dendrotoxin (Kv1.1, 1.2, 1.6), dendrotoxin-K (Kv1.1), or tityustoxin-Kα (Kv1.2) each blocked the inhibitory effect of DAMGO on mIPSCs. Double immunofluorescence labeling showed that some of the immunoreactivities of Kv1.1 and Kv1.2 were colocalized with synaptophysin in the BLA. This study provides new information that activation of presynaptic μ opioid receptors primarily attenuates GABAergic synaptic inputs to CeA-projecting neurons in the BLA through a signaling mechanism involving Kv1.1 and Kv1.2 channels.

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

2012 ◽  
Vol 107 (3) ◽  
pp. 1022-1031 ◽  
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.

scholarly journals Co-incident signalling between μ-opioid and M3 muscarinic receptors at the level of Ca2+ release from intracellular stores: lack of evidence for Ins(1,4,5)P3 receptor sensitization

2003 ◽  
Vol 375 (3) ◽  
pp. 713-720 ◽  
Author(s):  
Damien S. K. SAMWAYS ◽  
Wen-hong LI ◽  
Stuart J. CONWAY ◽  
Andrew B. HOLMES ◽  
Martin D. BOOTMAN ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Opioid Receptors ◽  
Receptor Agonist ◽  
Flash Photolysis ◽  
Receptor Activation ◽  
Scanning Confocal Microscopy ◽  
Rate Of Decay ◽  
Μ Opioid Receptor ◽  
Μ Opioid Receptors ◽  
Insp3 Receptor

Activation of Gi/Go-coupled opioid receptors increases [Ca2+]i (intracellular free-Ca2+ concentration), but only if there is concomitant Gq-coupled receptor activation. This Gi/Go-coupled receptor-mediated [Ca2+]i increase does not appear to result from further production of InsP3 [Ins(1,4,5)P3] in SH-SY5Y cells. In the present study, fast-scanning confocal microscopy revealed that activation of μ-opioid receptors alone by 1 μM DAMGO ([d-Ala, NMe-Phe, Gly-ol]-enkephalin) did not stimulate the InsP3-dependent elementary Ca2+-signalling events (Ca2+ puffs), whereas DAMGO did evoke Ca2+ puffs when applied during concomitant activation of M3 muscarinic receptors with 1 μM carbachol. We next determined whether μ-opioid receptor activation might increase [Ca2+]i by sensitizing the InsP3 receptor to InsP3. DAMGO did not potentiate the amplitude of the [Ca2+]i increase evoked by flash photolysis of the caged InsP3 receptor agonist, caged 2,3-isopropylidene-InsP3, whereas the InsP3 receptor sensitizing agent, thimerosal (10 μM), did potentiate this response. DAMGO also did not prolong the rate of decay of the increase in [Ca2+]i evoked by flash photolysis of caged 2,3-isopropylidene-InsP3. Furthermore, DAMGO did not increase [Ca2+]i in the presence of the cell-membrane-permeable InsP3 receptor agonist, InsP3 hexakis(butyryloxymethyl) ester. Therefore it appears that μ-opioid receptors do not increase [Ca2+]i through either InsP3 receptor sensitization, enhancing the releasable pool of Ca2+ or inhibition of Ca2+ removal from the cytoplasm.

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

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.

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

2004 ◽  
Vol 286 (4) ◽  
pp. R634-R641 ◽  
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.

An antisense oligodeoxynucleotide to μ-opioid receptors inhibits μ-opioid receptor agonist-induced analgesia in rats

1995 ◽  
Vol 275 (1) ◽  
pp. 105-108 ◽  
Author(s):  
Xiao-Hong Chen ◽  
Jill U. Adams ◽  
Ellen B. Geller ◽  
J.Kim DeRiel ◽  
Martin W. Adler ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Agonist ◽  
Antisense Oligodeoxynucleotide ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor ◽  
Μ Opioid Receptors

Exploring μ-Opioid Receptor Splice Variants as a Specific Molecular Target for New Analgesics

2020 ◽  
Vol 20 (31) ◽  
pp. 2866-2877
Author(s):  
Hirokazu Mizoguchi ◽  
Hideaki Fujii
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Effect ◽  
Splice Variants ◽  
Receptor Gene ◽  
Molecular Target ◽  
Μ Opioid Receptor ◽  
Dependence Liability ◽  
Μ Opioid Receptors

Since a μ-opioid receptor gene containing multiple exons has been identified, the variety of splice variants for μ-opioid receptors have been reported in various species. Amidino-TAPA and IBNtxA have been discovered as new analgesics with different pharmacological profiles from morphine. These new analgesics show a very potent analgesic effect but do not have dependence liability. Interestingly, these analgesics show the selectivity to the morphine-insensitive μ-opioid receptor splice variants. The splice variants, sensitive to these new analgesics but insensitive to morphine, may be a better molecular target to develop the analgesics without side effects.

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