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.

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.

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

scholarly journals TAN-67, a δ1-opioid receptor agonist, reduces infarct size via activation of Gi/oproteins and KATPchannels

1998 ◽  
Vol 274 (3) ◽  
pp. H909-H914 ◽  
Author(s):  
Jo El J. Schultz ◽  
Anna K. Hsu ◽  
Hiroshi Nagase ◽  
Garrett J. Gross
Keyword(s):  
Infarct Size ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Coronary Artery Occlusion ◽  
Receptor Activation ◽  
Artery Occlusion ◽  
Cardioprotective Effect ◽  
Area At Risk ◽  
Opioid Receptor Agonist ◽  
Δ Opioid Receptor

We have previously shown that delta (δ)-opioid receptors, most notably δ1, are involved in the cardioprotective effect of ischemic preconditioning (PC) in rats; however, the mechanism by which δ-opioid receptor-induced cardioprotection is mediated remains unknown. Therefore, we hypothesized that several of the known mediators of ischemic PC such as the ATP-sensitive potassium (KATP) channel and Gi/oproteins are involved in the cardioprotective effect produced by δ1-opioid receptor activation. To address these possibilities, anesthetized, open-chest Wistar rats were randomly assigned to five groups. Control animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. To demonstrate that stimulating δ1-opioid receptors produces cardioprotection, TAN-67, a new selective δ1-agonist, was infused for 15 min before the long occlusion and reperfusion periods. In addition, one group received 7-benzylidenenaltrexone (BNTX), a selective δ1-antagonist, before TAN-67. To study the involvement of KATPchannels or Gi/oproteins in δ1-opioid receptor-induced cardioprotection, glibenclamide (Glib), a KATPchannel antagonist, or pertussis toxin (PTX), an inhibitor of Gi/oproteins, was administered before TAN-67. Infarct size (IS) as a percentage of the area at risk (IS/AAR) was determined by tetrazolium stain. TAN-67 significantly reduced IS/AAR as compared with control (56 ± 2 to 27 ± 5%, n = 5, P < 0.05). The cardioprotective effect of TAN-67 was completely abolished by BNTX, Glib, and PTX (51 ± 3, 53 ± 5, and 61 ± 4%, n = 6 for each group, respectively). These results are the first to suggest that stimulating the δ1-opioid receptor elicits a cardioprotective effect that is mediated via Gi/oproteins and KATPchannels in the intact rat heart.

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.

Properties of TAN-67, a nonpeptide δ-opioid receptor agonist, at cloned human δ-and μ-opioid receptors

1995 ◽  
Vol 291 (2) ◽  
pp. 129-134 ◽  
Author(s):  
Richard J. Knapp ◽  
Robert Landsman ◽  
Sue Waite ◽  
Ewa Malatynska ◽  
Eva Varga ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Agonist ◽  
Opioid Receptor Agonist ◽  
Δ Opioid Receptor ◽  
Μ Opioid Receptors

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.

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