Pain, affective symptoms, and cognitive deficits in patients with cerebral dopamine dysfunction

Abstract

Converging preclinical, and human epidemiological, neuroimaging, and genetic evidence suggests a central role for dopamine neurotransmission in modulating pain perception and analgesia. Dysregulation in dopamine signaling may modulate the experience of pain both directly, by enhancing or diminishing the propagation of nociceptive signals, and indirectly, by influencing affective and cognitive processes, which affect the expectation, experience, and interpretation of nociceptive signals. Hypersensitivity to pain and high rates of comorbid chronic pain are common in disorders linked with deficits in dopamine system function, including disorders of mood and affect, substance abuse, and Parkinson disease. Hyposensitivity to pain, however, is common in patients with schizophrenia, which has been linked with excessive dopamine neurotransmission. Although patients are typically affected most by the primary symptoms of their disorders, alterations in pain perception may further increase the burden of their illness, compromising their quality of life. The present review focuses on this relationship, and discusses clinical and potential therapeutic implications for both patients with dopamine-related disorders and those with chronic pain syndromes.

Figure 1. Pleiotropic effect of the Val/Met polymorphism of the gene that codes for catechol-O-methyltransferase (COMT)

(A) Epigenetic events influence the expression of the COMT gene. (B) Expression of Val and Met polymorphisms of the COMT gene primarily affects the rate at which DA is catabolized in PFC, directly influencing synthesis of norepinephrine (NE) and epinephrine (Ep), which are also catabolized by COMT. In addition, the rate at which DA is catabolized has indirect affects on serotonin (5-HT) and μ-opioid (μOp) system activity. (C) Neurobiological intermediate phenotypes. Genetic variability in COMT polymorphisms has direct and indirect effects on DA activity across brain regions that comprise the DA system. This includes regions that have a relatively higher density of D1-like DA receptors (red), D2-like DA receptors (blue), or equal density of both receptor types (purple). There is a substantial overlap between these brain regions and those that are most commonly implicated in pain processing (outlined in black; Apkarian et al., 2004). Abbreviations: mc = motor cortex; cc = cingulate cortex; mfc = medial prefrontal cortex; ofc = orbitofrontal cortex; th = thalamus; gp = globus pallidus; sn = substantia nigra; am = amygdala; vta = ventral tegmental area; hi = hippocampus; c = caudate; p = putamen; in = insula; na = nucleus accumbens (D) Behavioral intermediate phenotypes. Neurobiological intermediate phenotypes as shown in C, can influence a cluster of behavioral intermediate phenotypes. (E) Clinical phenotypes. The cluster of behavioral phenotypes can result in differential clinical phenotypes, possibly through variations in environmental factors, including injury or psychosocial stressors.

Figure 2. Tonic–phasic regulation of DA transmission in the striatum and PFC

(A) Tonic/Phasic DA Transmission - striatum. Tonic DA release is dependent on slow, irregular spike activity of VTA DA neurons (1) and is modulated by glutamatergic afferents from the PFC (2). Tonic DA releases low levels of DA (5–20 nM concentrations) into the extrasynaptic space (3), where it is subject to a limited degree of catabolism by COMT (4). Phasic DA transmission is evoked by behaviorally salient stimuli, and is triggered by burst firing of VTA neurons (5), which release very high levels of DA into the synaptic cleft (M concentrations), where it stimulates postsynaptic D2-like DA receptors (6). Phasic DA is inactivated by removal from the synaptic cleft via rapid uptake by DAT (7), and therefore is not subject to catabolism by extrasynaptic COMT. Although tonic DA occurs in too low a concentration to stimulate intrasynaptic D2-like DA receptors, it stimulates presynaptic D2-like DA autoreceptors (8), which then inhibit phasic DA release (9). Therefore, tonic DA levels are controlled by an interaction of glutamatergic presynaptic stimulation and COMT catabolism; tonic DA in the extrasynaptic space in turn down regulates phasic DA release. (B) DA Transmission – PFC. Regulation of DA transmission in the PFC is markedly different. Burst firing of VTA DA neurons (1) releases high concentrations of DA into the synaptic cleft (2). Given that DA neurons in the PFC do not contain high levels of DAT, phasic DA transmission in the PFC is not restricted to the synaptic cleft. Instead, DA diffuses out of the synaptic cleft to stimulate nearby postsynaptic sites. Thus, in the PFC, COMT plays a more important role in the inactivation of DA following its release than in the striatum. Figure reproduced and adapted with permission from Bilder et al., 2004.

Figure 3. Activity of COMT differentially affects DA transmission in the PFC and the striatum

(A) COMT modulates DA transmission. DA in the PFC stimulates postsynaptic D1-like DA receptors, producing an excitatory effect on neuronal firing, which is largely limited by the catabolism of DA by COMT. This neuronal firing increases striatal glutamate release, which in turn, stimulates presynaptic DA receptors, promoting tonic DA release in striatal regions, such as nucleus accumbens (NAc). Tonic DA stimulates DA autoreceptors and decreases phasic DA release. COMT plays only a minor role in the catabolism of DA in the striatum. (B) The Met allele of COMT decreases its overall activity, resulting in slower catabolism of DA in the PFC, and thus greater PFC neuron firing. This, in turn leads to greater striatal glutamate transmission and thus greater tonic DA release, with lower levels of DA catabolism by COMT. The result is high levels of tonic DA and suppression of phasic DA. (C) In contrast, the Val allele of COMT increases its activity, and produces a markedly different series of events. High COMT activity in the PFC increases DA catabolism, thereby limiting D1-mediated excitation of PFC neurons. This diminishes glutamate-stimulated tonic DA release in the striatum, which is further limited by increased tonic DA metabolism by COMT. Phasic DA transmission is thus released from tonic DA modulation, resulting in abnormally high phasic DA response. Figure reproduced and adapted with permission from Bilder et al., 2004.