CC12, a P450/epoxygenase inhibitor, acts in the rat rostral, ventromedial medulla to attenuate morphine antinociception

Brain cytochrome P450 epoxygenases were recently shown to play an essential role in mediating the pain-relieving properties of morphine. To identify the CNS sites containing the morphine-relevant P450s, the effects of intracerebral (ic) microinjections of the P450 inhibitor CC12 were determined on morphine antinociception in rats. CC12 inhibited morphine antinociception when both drugs were injected into the rostral ventromedial medulla (RVM), but not following co-injections into the periaqueductal gray (PAG) or into the spinal subarachnoid space. In addition, intra-RVM CC12 pretreatment nearly completely blocked the effects of morphine following intracerebroventricular (icv) administration. Although morphine is thought to act in both the PAG and RVM by pre-synaptic inhibition of inhibitory GABAergic transmission, the present findings show that 1) the mechanism of morphine action differs between these two brainstem areas, and 2) P450 activity within the RVM is important for supraspinal morphine antinociception. Characterization of morphine-P450 interactions within RVM circuits will further enhance the understanding of the biochemistry of pain relief.

► Morphine activates brain μ opioid receptors to relieve pain through a cytochrome P450 epoxygenase mechanism.
► Morphine acts in several CNS areas, but the brain region(s) requiring cytochrome P450 activity are unknown.
► The P450 blocker CC12 inhibited morphine antinociception when injected into the rat rostral ventromedial medulla (RVM).
► Injections of CC12 into the periaqueductal gray or the spinal subarachnoid space did not affect morphine antinociception.
► These results show that cytochrome P450 activity within the RVM is essential for supraspinal morphine antinociception.