The major objective of the proposed research is to study the interaction of the brain reward system with the brain pain system and the effects of morphine on this interaction. The intracerebral implanting of two stimulating electrodes, one in a reward site and one in a nociceptive site allows the determination of the brain stimulation escape threshold (BSE) in the presence of rewarding brain stimulation as well as the determination of the brain stimulation reward threshold (BSR) in the presence of nociceptive stimulation. This interaction should help us understand how events that produce pleasure may alter the perception of pain and the corollary, how events that cause pain may alter the perception of pleasure. A dramatic example of the environment causing an impact on the modulation of pain was the report of the WWII establishment of a beachhead at Anzio in Italy. Many of the wounded refused morphine (75%) and it was reported that many were euphoric. The wound meant they would be evacuated and thus escape alive from one of the highest casualty battles of the war. The brain stimulation reward procedure allows a direct activation of that area of the brain that subserves usual pleasurable events, e.g., food, sex, drugs and most likely euphoria. Measurement of the BSE threshold in the presence of rewarding brain stimulation allows a study of the direct effect of the brain reward centers on the perception of pain. The reciprocal question, does pain change the sensitivity of a brain reward site? Out-patients in pain, who are not in a controlled environment and are using prescription opiates, may be a greater risk for addiction than the person without pain exposed to the same opiates. Thus, the pain itself may increase the rewarding value of morphine facilitating opiate addiction. The specific experiments will be carried out in rats in which two electrodes are surgically implanted in each animal, one in a reward site (the medial forebrain bundle) and the other in a pain site (mesencephalic reticular formation). In addition to determining the effect of rewarding brain stimulation on the perception of pain caused by stimulating a brain pain pathway, experiments will be conducted on the effect of rewarding brain stimulation on two types of peripheral pain stimulation. These involve a reflexive tail withdrawal to a heat stimulus (spinal) and instrumental escape from nociceptive foot shock (supra spinal). In all of the experiments thresholds will be determined using a modification of the classic method of limits.
The proposed experiments are designed to determine if activation of those parts of the brain that are related to pleasure will alter the perception of pain and whether such activation will enhance the analgesic effects of morphine. A second aspect of the research will determine if the presence of pain contributes to the development of addiction by making the effect of morphine more pleasurable. It is possible that such findings will contribute to the development of better analgesics that are less addicting.
| Kornetsky, Conan; Knapp, Clifford M; Tozier, Lisa et al. (2010) Medial forebrain stimulation enhances intracranial nociception and attenuates morphine analgesia suggesting the existence of an endogenous opioid antagonist. Pharmacol Biochem Behav 95:273-7 |
