Opioid therapy for chronic nonmalignant pain is of concern to both patients and physicians regarding addiction and abuse liability. Acute therapy with opioid medications poses limited risks of physical dependence, addiction or problems with diversion of medications. The potential for these adverse consequences greatly increases with long term opioid therapy. Chronic non-malignant pain is a major use of long-term opioid therapy, and often requires relatively large doses of opioids compared to acute pain management. Although much is known about the neurobiology of opioid reinforcement in normal animals, relatively little is known about how chronic pain alters the abuse liability of opioids. Preliminary data indicate that pain from nerve injury selectively attenuates the abuse liability of opioids, and that tolerance to the pain relieving actions of opioids develops rapidly with continuous drug access through self-administration. Furthermore, the abuse liability of opioids is modulated to a much greater extent by manipulating opioid receptors in the amygdala in rats with neuropathic pain compared to normal animals, suggesting that the basic mechanisms responsible for opioid self-administration differ in the presence of chronic pain. Understanding the role of opioid receptors in the amygdala in modulating the abuse liability of opioids selectivley in animals in the presence of chronic pain could lead to therapies that minimize the risk of addiction in pain patients. Studies are proposed to determine how activation of opioid receptors during self-administration produces distinct actions in the amygdala of nerve-injured rats compared to control animals. Neurochemical and pharmacological studies are proposed to determine which neurotransmitters and neurotransmitter receptors are differentially activated during opioid self-administration in normal rats or rats with neuropathic pain. In a second series of studies, the changing role of the amygdala during the development of tolerance to the analgesic effects of opioids will be determined during self-administered dose escalation in normal and nerve-injured rats to determine how the development of tolerance influences the regulation of this brain structure and its'role in the development of addiction. A third series of experiments are proposed that involve manipulating opioid receptors in brain areas known to be involved in classical nociceptive (anterior cingulate cortex, medial thalamus, rostoventral medulla) or reinforcement (nucleus accumbens, ventral tegmental area) pathways to determine which brain regions are primarily responsible for drug-seeking behaviors in the presence or absence of pain in rats. These studies will hopefully define mechanisms that modulate drug-seeking behaviors in the presence of neuropathic pain, and identify potential candidates for therapies that minimize the risk of addiction and physical dependence in pain patients.
