@article{77e6299c8fd241d9909b990cdd179d9d,
title = "Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla",
abstract = "Activation of neurons in the rostral ventral medulla, by electrical stimulation or microinjection of glutamate, produces antinociception. Microinjection of opioid compounds in this region also has an antinociceptive effect, indicating that opioids activate a medullary output neuron that exerts a net inhibitory effect on nociception. When given systemically in doses sufficient to produce antinocieeption, morphine produces distinct, opposing responses in two physiologically identifiable classes of rostral medullary neurons. {"}Off-cells{"} are activated, and have been proposed to inhibit nociceptive transmission. {"}On-cells{"} are invariably depressed, and may have a pro-nociceptive role. Although on-cell firing is also depressed by iontophoretically applied morphine, off-cells do not respond to morphine applied in this manner. The present study used local infusion of the μ-selective opioid peptide Tyr-d-Ala-Gly-MePhe-Gly-ol-enkephalin (DAMGO) within the rostral medulla to determine whether off-cells are activated by an opioid action within this region that is sufficient to produce a behaviorally measurable antinociception. Activity of on- and off-cells was recorded before and after local infusion of DAMGO noxious heat-evoked tail flick reflex was inhibited in 17 of 28 cases. On-cell firing was profoundly depressed, and this occurred irrespective of the antinociceptive effectiveness of the injection. Off-cells were activated following DAMGO microinjections, but only in experiments in which the tail flick reflex was inhibited. Both reflex inhibition and neuronal effects were reversed following systemic administration of naloxone. These observations thus confirm the role of the on-cell as the focus of direct opioid action within the rostral medulla, and strongly support the proposal that disinhibition of off-cells is central to the antinociception actions of opioids within this region.",
author = "Heinricher, {M. M.} and Morgan, {M. M.} and V. Tortorici and Fields, {H. L.}",
note = "Funding Information: from that followings ystemiac dministration.{\textquoteleft}I,n” - This conclusionis buttressebdy the finding that deedt,h eR VM is not requiredfo r systemmic orphine direct d&inhibitiono f off-cellsc an accountf or administratiotno producea ntin~i~ption.~It3 i*s , the antin~iceptivee ffectso f blocking GABA howevear, s ufficienstu bstratfeo r opioida ntinocicep transmissiowni thint heR VM.1{\textquoteright},{\textquoteleft}y*2{\textquoteright} tion.{\textquoteleft}~3~“{\textquoteleft}~{\textquoteleft}T2he2 p2rze senrte sultse stablishth ata n The reasonth atD AMGO microinjectiofna iledt o opioida ctionl ocalizedt o the RVM itselfa ctivates activateo ff-cellsa nd produceta il flick in~bitioni n off-cellsa, nd thatt hiso ccurso nly whent hed rugi s somee xperimenitss n ot clear.T he factt hato n-cell infusedin a dosea ndw itha distributionsu fficientto firing was uniformly depressedfo llowing RVM inhibit thet ail flick reflex. DAMGO microinj~tionsd emons~ateths at drug Neverthelesosf,f -cellsw erenot the only RVM was successfulleyj ectedfr om the pipettein these neurons showing changesi n activity following experimentsH.o wever,i t should be noted that DAMGO microinjectionth; e firing of on-cellsw as disinhibitionn eedn ot resulti n increasende uronal uniformlyd epressefdol lowingd ruga dministration.d ischargaen d variationsin the levelo f excitatory Like off-cellsa, substantiaplr oportiono f on-cellsh as drive in the off-cellp opulationm ay thus explain beens hownt o projectt o the spinalc ord,“2a nd it the variationsin antinociceptivpeo tencyo f opioid couldt husb ea rguedth ata removaol f a descendingm icroinjectionins thisr egion. influencefr om this cell classa ccountfso r thei nhi- bition of the tail flick. This inhibition of spinal nociceptivper ocessewso uldt henr educeth ea scend- ing flowo f nociceptivseig nalsa, ndt herebdyi sinhibit Theseo bservationtsh usc onfirmt he role of the the off-cell.T hat this cannotb e a completeex pla- on-cella st hef ocuso f directo pioida ctionw ithint he nationf or thep resenrte sultcsa nb ei nferredfr omt he RVM, and at thes amet imed em~nst~ptero found factt hatn on-selectivinea ctivationo f all neuronsin changeisn thef iring of off-cellsw hent hed oseso f RVM doesn oty ielda n antinociceptioann, dh asb een locallya ppliedo pioidsa res ucht hata behaviorally reportedto facilitater esponsetso noxiouss timu- measurabeleff ecits producedT.h is stronglysu pports lationi n somee xperimen2t5s24. .36-384T5h is means that then otiont hata disinhibitiono f off-cellbs ya n action suppressioonf on-cellf iringi s not in itselfs ufficient of opioidsw ithint heR VM is sufficientto producaen to yielda behaviorallmy easurabalen tinociception.antinociception. An activatioonf someo therc ellc lassin ther egionis also requiredI.n deed,a lthougho n-cell discharge Acknowledgements-This work was supported by PHS wasd epressebdy infusiono f DAMGO irrespectiveg rants DA05608a nd DA01949 and a Pain ResearchG rant of whethetrh e tail flick was inhibitedm, icroinjec-from the Bristol-Myers Squibb Company. M.M.M. was tions which failed to activateo ff-cellsd id not supported by DA05399. V.T. was supported by the resulti n inhibitiono f thet ail flick. Thus? disinhibi-y Tecnologicasa nd the FundacionP olar. We wish to thank VenezuelanC onsejoN ational de lnvestigacioneCs ientificas tion of off-cells is a crucial elementi n the Beth Budra far histologya nd artwork, and Julia Walbridge antinociceptivaec tiono f opioidsw ithin the RVM. for helpful commentso n the manuscript.",
year = "1994",
month = nov,
doi = "10.1016/0306-4522(94)90022-1",
language = "English (US)",
volume = "63",
pages = "279--288",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",
number = "1",
}