Reflex-related activation of putative pain facilitating neurons in rostral ventromedial medulla requires excitatory amino acid transmission

Heinricher, Mary M.; Roychowdhury, Swagata

doi:10.1016/s0306-4522(96)00683-5

Cited by 43 publications

(30 citation statements)

References 35 publications

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“…The vehicle alone was without effect (data not shown). markably seen in further reports from Dr. Heinricher's laboratory (Heinricher and Roychowdhury, 1997;Heinricher et al, 1999). Our data now implicate RVM ppOFQ/N (154 -181) in this dissociation.…”

Section: Discussionsupporting

confidence: 84%

Characterization of Rat Prepro-Orphanin FQ/Nociceptin_(154–181): Nociceptive Processing in Supraspinal Sites

Rossi¹,

Pellegrino²,

Shane³

et al. 2002

J Pharmacol Exp Ther

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Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the orphan receptor-like/ 3 -like opioid receptor clone, produces a variety of behavioral responses, including those associated with pronociception and antinociception. The OFQ/N precursor rattus-proOFQ (rppOFQ/N) contains several paired basic amino acids, which raises the possibility that post-translational processing can be responsible for the production of a number of additional biologically active peptide fragments. One of these putative peptides, rppOFQ/N (rppOFQ/N 154 -181 ), was examined for antinociceptive and pronociceptive processes in four brain sites involved in pain inhibition: the ventrolateral periaqueductal gray (vlPAG), the amygdala, the locus coeruleus (LC), and the rostroventromedial medulla (RVM). Endogenous rppOFQ/N 154 -181 was identified in each region. rppOFQ/N 154 -181 produced a dose-dependent antinociception in all four sites using the tailflick assay. Injections into misplaced cannula sites failed to exert effects. Antinociception in the four sites differed in their response to the opioid antagonist naloxone. Naloxone pretreatment completely blocked rppOFQ/N 154 -181-induced antinociception in the vlPAG and the amygdala, but not in the LC or RVM. In contrast rppOFQ/N 154 -181 was hyperalgesic in the LC and RVM, but not in the vlPAG or amygdala. rppOFQ/N 154 -181 also was compared with either its N-terminal 17-amino acid peptide (rppOFQ/N 154 -170 , also known as OFQ2) or its 8-amino acid C-terminal fragment (rppOFQ/N 174 -181 ). Although both rppOFQ/N 154 -181 and rppOFQ/N 154 -170 produced antinociception, the latter was less effective because the C-terminal fragment was inactive. Thus, rppOFQ/N 154 -181 has complex antinociceptive and pronociceptive actions within the brain, and the pharmacological specificity of its actions differs among supraspinal sites.Orphanin/FQ, or nociceptin (OFQ/N) (Meunier et al., 1995;Reinscheid et al., 1995), is generated from a larger proprotein, prepro-orphanin FQ/nociceptin (ppOFQ/N). Pharmacologically, the actions of OFQ/N are complex and appear to be contradictory ( Grisel et al., 1996;Mogil et al., 1996;King et al., 1997;Rossi et al., 1997). OFQ/N is hyperalgesic when given alone (Meunier et al., 1995;Reinscheid et al., 1995;Rossi et al., 1996Rossi et al., , 1997, and it can reverse opioid-induced antinociception Mogil et al., 1996;Tian et al., 1997). Furthermore, OFQ/N also has analgesic actions that become apparent when the hyperalgesic effects subside . The spinal administration of OFQ/N has similar antinociceptive effects (King et al., 1997). Additionally, a related peptide (rppOFQ/N 154 -170 ) that is homologous in the mouse and rat was also found to elicit a similar antinociceptive response (Rossi et al., 1998).Rat prepro OFQ/N (rppOFQ/N) contains several paired basic amino acids that can be proteolytically cleaved at multiple sites to potentially generate different peptides (Fig. 1). For instance, we have shown that a peptide corresponding to the full-length peptide rppOFQ/N 1...

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Section: Discussionsupporting

confidence: 84%

Characterization of Rat Prepro-Orphanin FQ/Nociceptin_(154–181): Nociceptive Processing in Supraspinal Sites

Rossi¹,

Pellegrino²,

Shane³

et al. 2002

J Pharmacol Exp Ther

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“…This model centers on the OFF-cell and the GABAergic input responsible for the OFF-cell pause. This model incorporates earlier evidence that -opioid and cannabinoid receptor 1 (CB 1 ) agonists act presynaptically to inhibit GABA release from terminals mediating the OFF-cell pause (Heinricher et al 1991(Heinricher et al , 1992Meng and Johansen 2004;Pan et al 1990;Vaughan et al 1999) and that morphine engages an excitatory input to OFF-cells (Heinricher et al 2001b). It also brings together the observations that improgan, which lacks affinity for known cannabinoid receptors, produces antinociception dependent on CB 1 receptors (Hough et al 2009b;Nalwalk et al 2006) and that CC12 blocks antinociception produced by both CB 1 -receptor agonists and improgan (Hough et al 2007).…”

Section: An Epoxygenase Model For Opioid Cannabinoid and Improgan Amentioning

confidence: 87%

“…The RVM was defined as the nucleus raphe magnus and adjacent reticular formation at the level of the facial nucleus. Recording sites were located within the RVM as in previous publications from this laboratory (Heinricher and Roychowdhury 1997;Heinricher and Tortorici 1994).…”

Section: Histologymentioning

confidence: 99%

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Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Heinricher

Maire²,

Lee³

et al. 2010

Journal of Neurophysiology

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Heinricher MM, Maire JJ, Lee D, Nalwalk JW, Hough LB. Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. J Neurophysiol 104: 3222-3230, 2010. First published October 6, 2010 doi:10.1152/jn.00681.2010. Many analgesic drugs, including -opioids, cannabinoids, and the novel nonopioid analgesic improgan, produce antinociception by actions in the rostral ventromedial medulla (RVM). There they activate pain-inhibiting neurons, termed "OFF-cells," defined by a nociceptive reflex-related pause in activity. Based on recent functional evidence that neuronal P450 epoxygenases are important for the central antinociceptive actions of morphine and improgan, we explored the convergence of opioid and nonopioid analgesic drug actions in RVM by studying the effects of the P450 epoxygenase inhibitor CC12 on the analgesic drug-induced activation of these OFF-cells and on behavioral antinociception. In rats lightly anesthetized with isoflurane, we recorded the effects of intraventricular morphine and improgan, with and without CC12 pretreatment, on tail flick latency and activity of identified RVM neurons: OFF-cells, ON-cells (pronociceptive neurons), and NEUTRAL cells (unresponsive to analgesic drugs). CC12 pretreatment preserved reflex-related changes in OFF-cell firing and blocked the analgesic actions of both drugs, without interfering with the increase in spontaneous firing induced by improgan or morphine. CC12 blocked suppression of evoked ON-cell firing by improgan, but not morphine. CC12 pretreatment had no effect by itself on RVM neurons or behavior. These data show that the epoxygenase inhibitor CC12 works downstream from receptors for both -opioid and improgan, at the inhibitory input mediating the OFF-cell pause. This circuit-level analysis thus provides a cellular basis for the convergence of opioid and nonopioid analgesic actions in the RVM. A presynaptic P450 epoxygenase may therefore be an important target for development of clinically useful nonopioid analgesic drugs.

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“…The electrophysiologic characteristics of the neurons of this region have been well characterized and strongly point to this region as a likely source of facilitation of nociceptive input (Fields et al, 1983;Fields and Heinricher, 1985;Fields, 1992). One neuronal class, labeled "ON" cells because of a firing burst recorded just before activation of a nocifensive response, is believed responsible for descending facilitation of nociception via both local interactions within the RVM and descending systems projecting to the spinal cord Heinricher et al, 1992;Heinricher and Roychowdhury, 1997). Manipulations that increase nociceptive responsiveness, thus indicating facilitation, also increase ON cell activity Kaplan and Fields, 1991;Morgan and Fields, 1994;Fields and Basbaum, 1999).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

et al. 2001

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Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing -opioid receptors were targeted with a single microinjection of saporin conjugated to the -opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin-saporin, but not dermorphin or saporin, significantly decreased cells expressing -opioid receptor transcript. RVM dermorphin, saporin, or dermorphin-saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM dermorphin-saporin failed to elicit the expected increase in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin-saporin against SNL-induced pain was blocked by ␤-funaltrexamine, a selective -opioid receptor antagonist, indicating specific interaction of dermorphin-saporin with the -opioid receptor. RVM microinjection of dermorphin-saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.

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Reflex-related activation of putative pain facilitating neurons in rostral ventromedial medulla requires excitatory amino acid transmission

Cited by 43 publications

References 35 publications

Characterization of Rat Prepro-Orphanin FQ/Nociceptin_(154–181): Nociceptive Processing in Supraspinal Sites

Characterization of Rat Prepro-Orphanin FQ/Nociceptin_(154–181): Nociceptive Processing in Supraspinal Sites

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

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Reflex-related activation of putative pain facilitating neurons in rostral ventromedial medulla requires excitatory amino acid transmission

Cited by 43 publications

References 35 publications

Characterization of Rat Prepro-Orphanin FQ/Nociceptin(154–181): Nociceptive Processing in Supraspinal Sites

Characterization of Rat Prepro-Orphanin FQ/Nociceptin(154–181): Nociceptive Processing in Supraspinal Sites

Physiological Basis for Inhibition of Morphine and Improgan Antinociception by CC12, a P450 Epoxygenase Inhibitor

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

Contact Info

Product

Resources

About

Characterization of Rat Prepro-Orphanin FQ/Nociceptin_(154–181): Nociceptive Processing in Supraspinal Sites

Characterization of Rat Prepro-Orphanin FQ/Nociceptin_(154–181): Nociceptive Processing in Supraspinal Sites