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.

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

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.

scholarly journals Activation of Peripheral μ-opioid Receptors by Dermorphin [d-Arg2, Lys4] (1–4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain

2016 ◽  
Vol 124 (3) ◽  
pp. 706-720 ◽  
Author(s):  
Vinod Tiwari ◽  
Fei Yang ◽  
Shao-Qiu He ◽  
Ronen Shechter ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Dynamic Range ◽  
Pain Treatment ◽  
Female Rats ◽  
Male Rats ◽  
Μ Opioid Receptor ◽  
Μ Opioid Receptors

Abstract Background Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects. Methods To determine the therapeutic value of peripheral μ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [d-Arg2, Lys4] (1–4) amide (DALDA), a hydrophilic, peripherally acting μ-opioid receptor agonist, in male and female rats with spinal nerve ligation–induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA’s possible mechanisms of action in male rats. Results DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral μ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber–mediated, but not A-fiber–mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the β-alanine–induced [Ca2+] increase (n = 300); capsaicin and β-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects. Conclusions These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.

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