Endogenous modulation of addiction: Chronic pain and the NMDA/NOS cascade

Opioid treatment for chronic pain is controversial due to abuse potential and perceived addiction potential. Because of perceptions of addiction from chronic opioid treatment for pain it is important to clearly understand the biological bases for a number of factors related to opioid therapy in the context of chronic pain, including the effectiveness of opioid treatment under distinct conditions chronic pain and alterations in the effectiveness of opioid treatment under distinct conditions of chronic opioid pharmacotherapy. One way to approach this question is to study the changes that occur with chronic pain and see how those changes parallel those that occur with opioid addiction. Our approach to address the questions raised above is to apply a combination of rodent models of pain and opioid self-administration. In the first phase of this study we examine changes in oral fentanyl self-administration under distinct conditions of chronic pain including inflammatory pain, neuropathic pain and an idiopathic pain model of sickle cell anemia. The second set of studies examines the potential for an endogenous modulator of the NMDA/NOS cascade to interact with adverse opioid events such as tolerance and addiction. We observed that mice with inflammatory pain, neuropathic pain and sickle cell anemia had differential fentanyl self-administration profiles following induction of mechanical hyperalgesia. In the second set of studies we observed that agmatine reduced opioid-induced tolerance and abolished self-administration behaviors. We also found that endogenous agmatine may have a neuroprotective effect on these opioid effects.