Chronic morphine exposure and the expression of heme oxygenase type 2.

Heme oxygenase (HO) catalyzes the formation of carbon monoxide (CO) and other products from heme. The CO formed has been shown to function as a neurotransmitter, and may be involved in nociceptive signaling. Heme oxygenase type 2 (HO-2) is the predominant form of HO in the CNS. The expression of nitric oxide synthase (NOS) which catalyzes the formation of a similar neurotransmitter nitric oxide (NO) from arginine is increased in the spinal cords of animals chronically exposed to morphine and other opioids. In these studies, we examined changes in expression of HO-2 which occur in spinal cord tissue of morphine tolerant mice. After 5 days of exposure to morphine, mice were observed to be profoundly tolerant to the analgesic effects of morphine. In experiments using Northern blotting we observed a 2.7-fold increase in HO-2 mRNA in homogenized spinal cord tissue. Additional experiments revealed a 3.1-fold increase in HO-2 protein which seemed to result from the increased expression of HO-2 in neurons in the dorsal horn region of the spinal cord. To complement our expression studies measured HO enzymatic activity in spinal cord homogenates and found a 2.1-fold increase in the tolerant animals. The functional significance of this increased expression and activity is as yet unclear, but may be involved in the acquisition of analgesic tolerance to opioids, dependence on opioids, or perhaps the hyperalgesia reported after chronic exposure to opioids.