Chronic Back Pain Is Associated with Alterations in Dopamine Neurotransmission in the Ventral Striatum.

Back pain is common in the general population, but only a subgroup of back pain patients develops a disabling chronic pain state. The reasons for this are incompletely understood, but recent evidence implies that both preexisting and pain-related variations in the structure and function of the nervous system may contribute significantly to the development of chronic pain. Here, we addressed the role of striatal dopamine (DA) D2/D3 receptor (D2/D3R) function in chronic non-neuropathic back pain (CNBP) by comparing CNBP patients and healthy controls using PET and the D2/D3R-selective radioligand [(11)C]raclopride. D2/D3R availability was measured at baseline and during a pain challenge, yielding in vivo measures of receptor availability (binding potential, BPND) and DA release (change in BPND from baseline to activated state). At baseline, CNBP patients demonstrated reductions in D2/D3R BPND in the ventral striatum compared with controls. These reductions were associated with greater positive affect scores and pain tolerance measures. The reductions in D2/D3R BPND were also correlated with µ-opioid receptor BPND and pain-induced endogenous opioid system activation in the amygdala, further associated with measures of positive affect, the affective component of back pain and pain tolerance. During the pain challenge, lower magnitudes of DA release, and therefore D2/D3R activation, were also found in the ventral striatum in the CNBP sample compared with controls. Our results show that CNBP is associated with adaptations in ventral striatal D2/D3R function, which, together with endogenous opioid system function, contribute to the sensory and affective-motivational features of CNBP. SIGNIFICANCE STATEMENT: The neural systems that underlie chronic pain remain poorly understood. Here, using PET, we provide insight into the molecular mechanisms that regulate sensory and affective dimensions of pain in chronic back pain patients. We found that patients with back pain have alterations in brain dopamine function that are associated with measures of pain sensitivity and affective state, but also with brain endogenous opioid system functional measures. These findings suggest that brain dopamine-opioid interactions are involved in the pathophysiology of chronic pain, which has potential therapeutic implications. Our results may also help to explain individual variation in susceptibility to opioid medication misuse and eventual addiction in the context of chronic pain.

Alterations in endogenous opioid functional measures in chronic back pain.

The absence of consistent end organ abnormalities in many chronic pain syndromes has led to a search for maladaptive CNS mechanisms that may explain their clinical presentations and course. Here, we addressed the role of brain regional µ-opioid receptor-mediated neurotransmission, one of the best recognized mechanisms of pain regulation, in chronic back pain in human subjects. We compared µ-opioid receptor availability in vivo at baseline, during pain expectation, and with moderate levels of sustained pain in 16 patients with chronic nonspecific back pain (CNBP) and in 16 age- and gender-matched healthy control subjects, using the µ-opioid receptor-selective radioligand [(11)C]carfentanil and positron emission tomography. We found that CNBP patients showed baseline increases in thalamic µ-opioid receptor availability, contrary to a previously studied sample of patients diagnosed with fibromyalgia. During both pain expectation and sustained pain challenges, CNBP patients showed regional reductions in the capacity to activate this neurotransmitter system compared with their control sample, further associated with clinical pain and affective state ratings. Our results demonstrate heterogeneity in endogenous opioid system functional measures across pain conditions, and alterations in both receptor availability and endogenous opioid function in CNBP that are relevant to the clinical presentation of these patients and the effects of opioid analgesics on µ-opioid receptors.

Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms.

This study investigates differences in µ-opioid receptor mediated neurotransmission in healthy controls and overnight-abstinent smokers, and potential effects of the OPRM1 A118G genotype. It also examines the effects of smoking denicotinized (DN) and average nicotine (N) cigarettes on the µ-opioid system. Positron emission tomography with (11)C-carfentanil was used to determine regional brain µ-opioid receptor (MOR) availability (non-displaceable binding potential, BPND) in a sample of 19 male smokers and 22 nonsmoking control subjects. Nonsmokers showed greater MOR BPND than overnight abstinent smokers in the basal ganglia and thalamus. BPND in the basal ganglia was negatively correlated with baseline craving levels and Fagerström scores. Interactions between group and genotype were seen in the nucleus accumbens bilaterally and the amygdala, with G-allele carriers demonstrating lower BPND in these regions, but only among smokers. After smoking the DN cigarette, smokers showed evidence of MOR activation in the thalamus and nucleus accumbens. No additional activation was observed after the N cigarette, with a mean effect of increases in MOR BPND (i.e., deactivation) with respect to the DN cigarette effects in the thalamus and left amygdala. Changes in MOR BPND were related to both Fagerström scores and changes in craving. This study showed that overnight-abstinent smokers have lower concentrations of available MORs than controls, an effect that was related to both craving and the severity of addiction. It also suggests that nicotine non-specific elements of the smoking experience have an important role in regulating MOR-mediated neurotransmission, and in turn modulating withdrawal-induced craving ratings.