Functional Interaction Between TRPV1 and μ-Opioid Receptors in the Descending Antinociceptive Pathway Activates Glutamate Transmission and Induces Analgesia

2009 ◽  
Vol 101 (5) ◽  
pp. 2411-2422 ◽  
Author(s):  
Sabatino Maione ◽  
Katarzyna Starowicz ◽  
Luigia Cristino ◽  
Francesca Guida ◽  
Enza Palazzo ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Rostral Ventromedial Medulla ◽  
Neuron Activity ◽  
Opioid Receptor Antagonists ◽  
Ventromedial Medulla ◽  
Output Neurons ◽  
Μ Opioid Receptors ◽  
Μ Receptor

The transient receptor potential vanilloid-1 (TRPV1) receptor is involved in peripheral and spinal nociceptive processing and is a therapeutic target for pain. We have shown previously that TRPV1 in the ventrolateral periaqueductal gray (VL-PAG) tonically contributes to brain stem descending antinociception by stimulating glutamate release into the rostral ventromedial medulla and off neuron activity. Because both opioid and vanilloid systems integrate and transduce pain sensation in these pathways, we studied the potential interaction between TRPV1 and μ-opioid receptors in the VL-PAG–rostral ventromedial medulla (RVM) system. We found that the TRPV1 agonist, capsaicin, and the μ-receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin, when coadministered into the ventrolateral-PAG at doses nonanalgesic per se, produce 1) antinociception in tests of thermal nociception; 2) stimulation of glutamate release into the RVM; and 3) inhibition of on neuron activity in the RVM. These effects were all antagonized by the TRPV1 and opioid receptor antagonists 5′-iodo-resiniferatoxin and naloxone, respectively, thus suggesting the existence of a TRPV1–μ-opioid interaction in the VL-PAG–RVM system. By using double immunofluorescence techniques, we found that TRPV1 and μ-opioid receptors are coexpressed in several neurons of the VL-PAG. These findings suggest that μ-receptor activation not only acts on inhibitory neurons to disinhibit PAG output neurons but also interacts with TRPV1 activation at increasing glutamate release into the RVM, possibly by acting directly on PAG output neurons projecting to the RVM.

Pretreatment of rats with the irreversible μ-receptor antagonist, β-FNA, fails to prevent naltrexone-induced upregulation of μ-opioid receptors

1990 ◽  
Vol 29 (9) ◽  
pp. 805-810 ◽  
Author(s):  
R.B. Rothman ◽  
J.B. Long ◽  
V. Bykov ◽  
A.E. Jacobson ◽  
K.C. Rice ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Opioid Receptors ◽  
Μ Opioid Receptors ◽  
Μ Receptor

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.

scholarly journals Hyperalgesia and sensitization of dorsal horn neurons following activation of NK-1 receptors in the rostral ventromedial medulla

2017 ◽  
Vol 118 (5) ◽  
pp. 2727-2744 ◽  
Author(s):  
Sergey G. Khasabov ◽  
Patrick Malecha ◽  
Joseph Noack ◽  
Janneta Tabakov ◽  
Glenn J. Giesler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Receptor Activation ◽  
Rostral Ventromedial Medulla ◽  
Dorsal Horn Neurons ◽  
Descending Modulation ◽  
Ventromedial Medulla ◽  
Neurokinin 1 ◽  
Wdr Neurons

Neurons in the rostral ventromedial medulla (RVM) project to the spinal cord and are involved in descending modulation of pain. Several studies have shown that activation of neurokinin-1 (NK-1) receptors in the RVM produces hyperalgesia, although the underlying mechanisms are not clear. In parallel studies, we compared behavioral measures of hyperalgesia to electrophysiological responses of nociceptive dorsal horn neurons produced by activation of NK-1 receptors in the RVM. Injection of the selective NK-1 receptor agonist Sar9,Met(O2)11-substance P (SSP) into the RVM produced dose-dependent mechanical and heat hyperalgesia that was blocked by coadministration of the selective NK-1 receptor antagonist L-733,060. In electrophysiological studies, responses evoked by mechanical and heat stimuli were obtained from identified high-threshold (HT) and wide dynamic range (WDR) neurons. Injection of SSP into the RVM enhanced responses of WDR neurons, including identified neurons that project to the parabrachial area, to mechanical and heat stimuli. Since intraplantar injection of capsaicin produces robust hyperalgesia and sensitization of nociceptive spinal neurons, we examined whether this sensitization was dependent on NK-1 receptors in the RVM. Pretreatment with L-733,060 into the RVM blocked the sensitization of dorsal horn neurons produced by capsaicin. c-Fos labeling was used to determine the spatial distribution of dorsal horn neurons that were sensitized by NK-1 receptor activation in the RVM. Consistent with our electrophysiological results, administration of SSP into the RVM increased pinch-evoked c-Fos expression in the dorsal horn. It is suggested that targeting this descending pathway may be effective in reducing persistent pain. NEW & NOTEWORTHY It is known that activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM), a main output area for descending modulation of pain, produces hyperalgesia. Here we show that activation of NK-1 receptors produces hyperalgesia by sensitizing nociceptive dorsal horn neurons. Targeting this pathway at its origin or in the spinal cord may be an effective approach for pain management.

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.

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