Opioid receptor modulation of GABAergic and serotonergic spinally projecting neurons of the rostral ventromedial medulla in mice

2011 ◽  
Vol 106 (2) ◽  
pp. 731-740 ◽  
Author(s):  
Nigel P. Pedersen ◽  
Christopher W. Vaughan ◽  
MacDonald J. Christie
Keyword(s):  
Spinal Cord ◽  
Opioid Receptor ◽  
Tryptophan Hydroxylase ◽  
Rostral Ventromedial Medulla ◽  
Inhibitory Influence ◽  
Receptor Modulation ◽  
Outward Currents ◽  
Neuronal Mechanisms ◽  
Ventromedial Medulla

The rostral ventromedial medulla (RVM) is an important site of opioid actions and forms part of an analgesic pathway that projects to the spinal cord. The neuronal mechanisms by which opioids act within this brain region remain unclear, particularly in relation to the neurotransmitters GABA and serotonin. In the present study, we examined serotonergic and GABAergic immunoreactivity, identified using immunohistochemistry for tryptophan hydroxylase (TPH) and glutamate decarboxylase (GAD), in combination with in vitro whole cell patch clamping to investigate the role of opioids on the mouse RVM with identified projections to the spinal cord. Tyr-d-Ala-Gly- N-Me-Phe-Gly-ol enkephalin (DAMGO) produced μ-opioid receptor-mediated outward currents in virtually all TPH-immunoreactive projecting neurons and GAD-immunoreactive nonprojecting neurons (87% and 86%). The other groups of RVM neurons displayed mixed responsiveness to DAMGO (40–68%). Deltorphin II and U-69593 produced δ- and κ-opioid receptor-mediated outward currents in smaller subpopulations of RVM neurons, with many of the δ-opioid responders forming a subpopulation of μ-opioid-sensitive GABAergic nonprojecting neurons. These findings are consistent with prior electrophysiological and anatomic studies in the rat RVM and indicate that both serotonergic and GABAergic RVM neurons mediate the actions of μ-opioids. Specifically, μ-opioids have a direct postsynaptic inhibitory influence over both GABAergic and serotonergic neurons, including those that project to the dorsal spinal cord.

scholarly journals Rostral Ventromedial Medulla Neurons That Project to the Spinal Cord Express Multiple Opioid Receptor Phenotypes

2002 ◽  
Vol 22 (24) ◽  
pp. 10847-10855 ◽  
Author(s):  
Silvia Marinelli ◽  
Christopher W. Vaughan ◽  
Stephen A. Schnell ◽  
Martin W. Wessendorf ◽  
MacDonald J. Christie
Keyword(s):  
Spinal Cord ◽  
Opioid Receptor ◽  
Rostral Ventromedial Medulla ◽  
Ventromedial Medulla

scholarly journals Kappa opioids inhibit the GABA/glycine terminals of rostral ventromedial medulla projections in the superficial dorsal horn of the spinal cord

2021 ◽  
Author(s):  
Yo Otsu ◽  
Karin Aubrey
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Kappa Opioid Receptor ◽  
Rostral Ventromedial Medulla ◽  
Projection Neurons ◽  
Superficial Dorsal Horn ◽  
Opioid Receptor Agonist ◽  
Ventromedial Medulla

Background and Purpose: Descending projections from neurons in the rostral ventromedial medulla (RVM) make synapses within the superficial dorsal horn of the spinal cord that are involved in acute nociception and the development of chronic pain and itch. In addition, this projection plays an important role in mediating the analgesic effects of opioids. However, our knowledge about the spinal synaptic targets of RVM projections and their modulation by opioids is unknown. Experimental Approach: We used ex vivo optogenetic stimulation of RVM descending fibres and whole-cell patch-clamp recordings from superficial dorsal horn (SDH) neurons to identify the target neurons and to investigate their descending synaptic inputs. Key Results: We demonstrate that SDH neurons are targeted by descending GABA/glycine inhibitory inputs from the RVM, although glycinergic inputs predominate. These SDH neurons had diverse morphological and electrical properties. This inhibitory synapse was presynaptically suppressed by the kappa opioid receptor agonist U69593. By contrast, the mu-opioid receptor agonist DAMGO inhibited only a subset of RVM-SDH synapses, acting both pre- and postsynaptically, while the delta-opioid receptor agonist deltorphin II had little effect. Conclusion and Implications: Developing reliable and effective alternatives to opioid analgesics requires a detailed, mechanistic understanding of how opioids interact with nociceptive circuits. This study selectively and systematically characterises the synaptic connections between RVM projection neurons and their SDH targets to advance our knowledge of how this descending projection is organised and modulated. In addition, it improves our understanding of how opioids alter spinal pathways involved in the sensations of pain and itch.

Kappa Opioids Inhibit Physiologically Identified Medullary Pain Modulating Neurons and Reduce Morphine Antinociception

2005 ◽  
Vol 93 (3) ◽  
pp. 1138-1144 ◽  
Author(s):  
I. D. Meng ◽  
J. P. Johansen ◽  
I. Harasawa ◽  
H. L. Fields
Keyword(s):  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Rostral Ventromedial Medulla ◽  
Tail Flick ◽  
Direct Inhibition ◽  
Postsynaptic Inhibition ◽  
Kappa Opioids ◽  
Ventromedial Medulla

Microinjection of kappa opioid receptor (KOR) agonists into the rostral ventromedial medulla (RVM) attenuates mu-opioid receptor mediated antinociception and stress-induced analgesia, yet is also reported to have an analgesic effect. To determine how KOR agonists produce both antinociceptive and antianalgesic actions within the RVM, the KOR agonist U69593 was microinjected directly into the RVM while concurrently monitoring tail flick latencies and RVM neuronal activity. Among RVM neurons recorded in vivo, two types show robust changes in activity just prior to the nocifensive tail flick reflex: on cells burst just prior to a tail flick and their activity is pronociceptive, whereas off cells pause just prior to the tail flick and their activity is antinociceptive. Although RVM microinjection of U69593 did not affect tail flick latencies on its own, it did attenuate the on cell burst, an effect blocked by co-injection of the KOR antagonist, nor-binaltorphimine (nor-BNI). Furthermore, U69593 inhibited ongoing activity in subsets of off cells (4/11) and neutral cells (3/9). Microinjection of U69593 into the RVM also attenuated morphine antinociception and suppressed the excitation of off cells. Together with previous in vivo and in vitro studies, these results are consistent with the idea that KOR agonists can be either pronociceptive through direct inhibition of off cells, or antianalgesic through both postsynaptic inhibition and presynaptic inhibition of glutamate inputs to RVM off cells.

Identification of a subsurface area in the ventral medulla sensitive to local changes in PCO2

1992 ◽  
Vol 72 (2) ◽  
pp. 439-446 ◽  
Author(s):  
F. G. Issa ◽  
J. E. Remmers
Keyword(s):  
Spinal Cord ◽  
Neural Activity ◽  
Ventral Surface ◽  
Sudden Increase ◽  
Neonatal Rats ◽  
Central Chemoreceptors ◽  
Ventral Medulla ◽  
Ventromedial Medulla ◽  
Stimulation Of

The exact location of the central respiratory chemoreceptors sensitive to changes in PCO2 has not yet been determined. To avoid the confounding effects of the cerebral circulation, we used the in vitro brain stem-spinal cord of neonatal rats (1–5 days old) to identify areas within 500 microns of the ventral surface of the medulla where changes in PCO2 evoked a sudden increase in the rate of respiratory neural activity. The preparation was superfused with mock cerebrospinal fluid (CSF) while maintained at constant temperature (26 +/- 1 degrees C) and pH (7.34). Respiratory frequency increased linearly with decreases in superfusate pH (r2 = 0.92, P less than 0.001), indicating that the respiratory circuitry for the detection of CO2 and stimulation of breathing was intact in this preparation. The search for central chemoreceptors was performed with a specially designed micropipette that allowed microejection of 2–10 nl of mock CSF equilibrated with different CO2-O2 gas mixtures. The pipette was advanced in 50- to 100-microns steps by use of a microdrive to a maximum depth of 500 microns from the surface of the ventral medulla. Depending on the location of the micropipette, ejection of CO2-acidified mock CSF at depths of 100–350 microns below the ventral surface of the medulla stimulated neural respiratory output. Using this response as an indication of the location of central respiratory chemoreceptors, we found that chemoreceptive elements were located in a column in the ventromedial medulla extending from the hypoglossal rootlets caudally to an area 0.75 mm caudal to VI nerve in the rostral medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

δ-opioid receptor-mediated actions on rostral ventromedial medulla neurons

Neuroscience ◽  
2005 ◽  
Vol 132 (2) ◽  
pp. 239-244 ◽  
Author(s):  
S. Marinelli ◽  
M. Connor ◽  
S.A. Schnell ◽  
M.J. Christie ◽  
M.W. Wessendorf ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Rostral Ventromedial Medulla ◽  
Ventromedial Medulla ◽  
Δ Opioid Receptor

Differential Effects of Opioids on Sacrocaudal Afferent Pathways and Central Pattern Generators in the Neonatal Rat Spinal Cord

2007 ◽  
Vol 97 (4) ◽  
pp. 2875-2886 ◽  
Author(s):  
D. Blivis ◽  
G. Z. Mentis ◽  
M. J. O'Donovan ◽  
A. Lev-Tov
Keyword(s):  
Spinal Cord ◽  
Opioid Receptor ◽  
Central Pattern Generators ◽  
Rhythmic Activity ◽  
Ventral Horn ◽  
Neonatal Rat ◽  
Experimental Chamber ◽  
Afferent Pathways ◽  
Anatomical Basis ◽  
Ventromedial Medulla

The effects of opioids on sacrocaudal afferent (SCA) pathways and the pattern-generating circuitry of the thoracolumbar and sacrocaudal segments of the spinal cord were studied in isolated spinal cord and brain stem-spinal cord preparations of the neonatal rat. The locomotor and tail moving rhythm produced by activation of nociceptive and nonnociceptive sacrocaudal afferents was completely blocked by specific application of the μ-opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate salt (DAMGO) to the sacrocaudal but not the thoracolumbar segments of the spinal cord. The rhythmic activity could be restored after addition of the opioid receptor antagonist naloxone to the experimental chamber. The opioid block of the SCA-induced rhythm is not due to impaired rhythmogenic capacity of the spinal cord because a robust rhythmic activity could be initiated in the thoracolumbar and sacrocaudal segments in the presence of DAMGO, either by stimulation of the ventromedial medulla or by bath application of N-methyl-d-aspartate/serotonin. We suggest that the opioid block of the SCA-induced rhythm involves suppression of synaptic transmission through sacrocaudal interneurons interposed between SCA and the pattern-generating circuitry. The expression of μ opioid receptors in several groups of dorsal, intermediate and ventral horn interneurons in the sacrocaudal segments of the cord, documented in this study, provides an anatomical basis for this suggestion.

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.

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