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

Abstract

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.

A possible neural mechanism for photosensitivity in chronic pain

“…Light activated a subset of RVM ON-cells and suppressed the firing of a subset of OFF-cells. Since the net effect of ON-cell activation is pro-nociceptive and aversive, while the net effect of OFF-cell activation is anti-nociceptive, 28,30,33 light exposure tipped the balance in this system to a more pro-nociceptive state.…”

Optogenetic Evidence for a Direct Circuit Linking Nociceptive Transmission through the Parabrachial Complex with Pain-Modulating Neurons of the Rostral Ventromedial Medulla (RVM)

“…Both classes receive noxious inputs: ON-cells are activated, leading to a “burst” of activity associated with behavioral responses to noxious stimulation, while OFF-cell firing is suppressed, producing a “pause” in any ongoing activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function (Fields and Heinricher, 1985; Heinricher et al, 2010), the pathways through which nociceptive information is conveyed to the RVM have only recently begun to be delineated, with PB identified as one important relay (Roeder et al, 2016). …”

Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons

“…Following NPY administration, OFF-cells continued to display the same relative decrease in firing at the withdrawal, suggesting that the NPY-mediated increase in spontaneous activity is primarily post-synaptic. This observation of increased spontaneous activity with a preserved reflex-related change in firing lends strength to the idea that drugs must block the GABAergic input mediating the OFF-cell pause for RVM-mediated analgesia (Heinricher et al, 1991, Heinricher et al, 1994, Heinricher et al, 2010). At the same time, this finding also shows that an increase in the output of the OFF-cell population is sufficient to suppress hyperalgesia without producing analgesia.…”

“…This region exerts bidirectional control of nociception through two physiologically defined populations of neurons, the “ON-cells” and “OFF-cells.” ON-cells are activated by stimuli that evoke nocifensive withdrawal responses, and direct pharmacological activation of the ON-cell population produces behavioral hyperalgesia (Fields and Heinricher, 1985, Heinricher and Neubert, 2004, Neubert et al, 2004, Kincaid et al, 2006). By contrast, OFF-cells are inhibited by stimuli that evoke nocifensive withdrawal responses, and pharmacological activation of these neurons produces hypoalgesia or analgesia (Heinricher et al, 1994, Heinricher et al, 2010). Considerations of the role of the RVM in persistent pain have therefore focused on the ON-cells.…”