[Abstract Title]. - Society for Neuroscience

Abstract: It is well established that morphine acts at κ-opioid receptors in the brain and spinal
cord to produce analgesia, but the biochemical cascade following receptor activation remains
unclear. Recently, a new cimetidine derivative named CC12 was reported to inhibit morphine
antinociception by an action independent of opioid receptors (Hough et al., 2007). Because CC12
has been found to have potent cytochrome P450- (CYP-) inhibitory activity (Stadel et al., 2008),
the effects of several CYP and epoxygenase inhibitors were presently studied on morphine
antinociception in rats. Nociceptive thresholds were assessed with the hot-plate and tail-flick
tests. Intracerebroventricular (i.c.v.) administration of morphine (20 κg) produced significant
increases in both tail-flick and hot-plate latencies, effects which were nearly completely
abolished by pretreatment with a very low dose (10 nmol i.c.v.) of the CYP inhibitor miconazole.
However, miconazole had activity at κ, δ, and θ- opioid, as well as histamine H3 receptors (Ki =
0.6 - 4.5 µM ). A new CC12 derivative, MW-06-25 (N-((4-iodobenzyl) thiomethyl)-imidazole),
was a potent CYP inhibitor in vitro (CYP2C19, IC50 = 19.1 nM), and blocked morphine
antinociception in vivo (10 nmol; i.c.v.). MW-06-25 (10 µM) also lacked activity at arachidonate
cyclooxygenase, 12-lipoxygenase, opioid receptors and H3 receptors. Furthermore, pretreatment
with the epoxygenase inhibitor MS-PPOH (a non-imidazole, fatty-acid derivative, 30 and 300
nmol; i.c.v.) resulted in significant, dose-dependent inhibition of morphine antinociception.
These findings suggest a role for the PLA2/ arachidonic acid/ epoxygenase pathway in κ-opioid
mediated morphine antinociceptive signaling. Elucidation of morphine‟s downstream mediators
will enhance understanding of the biochemistry of analgesic circuits.
Disclosures: J.L. Conroy, None; J. Nalwalk , None; M.A. VanAlstine, None; B.I. Knapp,
None; J.M. Bidlack, None; O.P. Zuiderveld, None; R. Leurs, None; Z. Shan, None; S. Zhang,
None; M.P. Wentland, None; L.B. Hough, None.
Poster
270. Pain: Opioids and Other Analgesics II
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 270.18/HH17
Topic: D.08.r. Opioids and other analgesics
Support: Department of Anesthesiology
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