The long-term objective of this research is to understand how morphine acts acutely in the central nervous system to produce analgesia and how these effects are modified by chronic pain and/or morphine exposure, to produce tolerance. Previous investigations led to a model, which postulates that 1) the analgesic effect of morphine at the spinal cord is normally suppressed by a mechanism originating in the brain, and that 2) this suppression is eliminated when the spinal cord is transected or when morphine is simultaneously administered to the brain and the spinal cord. The removal of this inhibitory influence on the spinal effect of morphine accounts for the profound potency of systemically administered morphine relative to the effect of morphine at each of these two sites separately.
The specific aim of the proposed experiments is to determine which transmitter(s) are responsible for the postulated inhibition exerted by the brain on the analgesic effect of spinal morphine. Representative agonists and antagonists of several transmitter systems will be administered to the spinal cord (intrathecally) of intact rats and rats that have received an acute spinal transection. These compounds will be injected 1)alone - to determine whether they are directly involved in pain (nociceptive) processes at the level of the spinal cord and 2) in combination with a) spinal morphine b) spinal and supraspinal morphine and c) systemic morphine - to determine whether they modulate opiate analgesia. The nociceptive response will consist of the tail withdrawal reflex (tail flick) to a noxious thermal stimulus. The transmitter systems that will be examined include the 1) opioids 2) adenosine 3) gamma-amino butyric acid 4) glutamate 5) acetylcholine 6) serotonin and 7) norepinephrine. If morphine-induced analgesia is modified, as predicted, by compounds that act through any of these systems, then our knowledge of opiate analgesia will be enhanced and subsequent studies can explore the role of these transmitters in opiate tolerance.
Showing the most recent 10 out of 20 publications
