Experimental evidence points to important interindividual and sex differences in responses to drugs of abuse, stressors, and in the function of neurotransmitter systems thought to mediate those responses. Specifically, variations in the function or responses of dopaminergic (DA) and opioid systems are known to be centrally implicated in the development of opiate abuse and dependence. Recent data from our laboratory and others using PET and selective radiotracers targeting mu-opioid and DA-D2 receptors has also shown that these neurotransmitter systems are involved in the responses and regulation of pain. Data in healthy subjects demonstrates opposing effects of these neurotransmitters, with DA-D2 neurotransmission enhancing, and mu-opioid suppressing, pain reporting and pain sensitivity measures. A modulation of DA-D2 receptors (increases) and mu-opioid receptors (reduced) has been shown in clinical chronic pain samples, further associated with higher levels of pain reporting and pain sensitivity. In response to RFA-DA-06-005, the present application builds on that initial data to examine the effects of chronic pain and opioid administration on the function of these neurotransmitter systems. It is proposed to study a well-charaterized sample of patients diagnosed with chronic lumbar pain either treated or not with opiates and an age- and sex- matched sample of healthy controls. We are to examine the effect of chronic pain and opiate treatment on baseline levels of mu-opioid and DA-D2 receptors in vivo. In addition, we propose to utilize a pain challenge mimicking a flair in the pain signal to determine the involvement of DA and mu-opioid release on behavioral responses to variations in pain in these three samples. These neurochemical measures will then be related to individual differences in prospectively rated pain, analgesic requirements, subjective effects of cumulative doses of the prototypical mu-opioid agonist fentanyl, and rates of discounting in a opiate and monetary delay discounting paradigm. We are not proposing to study patients known to misuse or abuse opiates, or dependent on opiates, as concurrent abuse or dependence would confound the effects of chronic pain and therapeutic opiate administration. However, these initial studies will provide with valuable information in humans, linking the function of opioid and DA neurotransmission with factors and constructs known to confer an elevated risk for the subsequent development of opioid misuse and abuse (e.g., pain variability, distress in responses to variations in pain, impulsive choice and rewarding responses to acute opiate administration).
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