Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor

Mary Heinricher, Jennifer J. Maire, Delaina Lee, Julia W. Nalwalk, Lindsay B. Hough

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Many analgesic drugs, including μ-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 μ-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.

Original languageEnglish (US)
Pages (from-to)3222-3230
Number of pages9
JournalJournal of Neurophysiology
Volume104
Issue number6
DOIs
StatePublished - Dec 2010

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Morphine
Non-Narcotic Analgesics
Analgesics
Opioid Analgesics
Neurons
Reflex
Cannabinoids
Inhibition (Psychology)
SKF 92374
Isoflurane
Opioid Receptors
Tail
Pain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. / Heinricher, Mary; Maire, Jennifer J.; Lee, Delaina; Nalwalk, Julia W.; Hough, Lindsay B.

In: Journal of Neurophysiology, Vol. 104, No. 6, 12.2010, p. 3222-3230.

Research output: Contribution to journalArticle

Heinricher, Mary ; Maire, Jennifer J. ; Lee, Delaina ; Nalwalk, Julia W. ; Hough, Lindsay B. / Physiological basis for inhibition of morphine and improgan antinociception by CC12, a P450 epoxygenase inhibitor. In: Journal of Neurophysiology. 2010 ; Vol. 104, No. 6. pp. 3222-3230.
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