Alterations in Endogenous Opioid Neurotransmission Associated with Acute and Long-term Use of Drugs of Abuse.

The endogenous opioid neurotransmitter system (EOS) has been implicated in a wide array of behavioral processes, including reinforcement, pain modulation, mood disorders, social interactions, and the placebo effect. These intertwining factors make an understanding of the EOS’s role crucial for developing effective therapies for a range of disorders. We used positron emission tomography to investigate whether acute and long-term administration of two drugs of abuse, nicotine and opioid analgesics, are associated with alterations in endogenous mu-opioid neurotransmission. We found that compared to healthy controls, overnight-abstinent smokers showed significant decreases in mu-opioid receptor (MOR) availability in the thalamus and bilateral basal ganglia, regions previously implicated in drug reinforcement and addiction. Moreover, these alterations in neurotransmission were associated with measures of both nicotine dependence and craving. When overnight-abstinent smokers were subsequently given a denicotinized (DN) cigarette to smoke, they showed decreases in MOR availability in the right nucleus accumbens and thalamus, likely related to endogenous opioid release in response to the expectation of receiving nicotine. This placebo effect associated with the DN cigarette appeared to mask the effects of the regular nicotine cigarette smoked afterwards. We also examined how opioid analgesics affect MOR neurotransmission in patients with chronic back pain. Our results indicated that decreases in the integrity of the endogenous opioid system, as indicated by a reduced ability to release endogenous opioids in response to pain, were associated with both higher clinical back pain ratings and with greater hedonic responses to the administration of an exogenous opioid drug. Patients using opioid analgesics for at least one year showed decreased experimental pain-induced MOR activation and a lower number of available free MORs at baseline in regions of the brain implicated in pain modulation and drug abuse, such as the nucleus accumbens and amygdala. With the high prevalence of nicotine smoking, as well as the increasing use of opioid analgesics, it is crucial to understand how endogenous opioid mechanisms are implicated in the reinforcing and long-term effects of these drugs. This knowledge will help suggest avenues to explore while determining what treatments may be most successful in individual patients.PhDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120787/1/emilybn_1.pd