Nucleus Accumbens Motivation during Chronic Pain

Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Nucleus Accumbens Motivation during Chronic Pain

Science 1 August 2014: Vol. 345 no. 6196 pp. 535-542

Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens

Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.

Department of Pharmacology, School of Medicine, University of Maryland, 655 West Baltimore Street, Baltimore, MD 21201, USA.

Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

[paraphrase]

Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1–triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.

Symptoms that profoundly affect the quality of life of patients with chronic pain include fatigue, reductions in pre-pain activities, and depression. A common feature of these symptoms is a decrease in the motivation to undertake and to successfully complete goal-directed actions. Although in the setting of acute pain these features may be adaptive by limiting activity during the healing process and reducing the likelihood of future injury by motivating avoidance, they are a major source of the morbidity accompanying chronic pain syndromes. Here, we hypothesize that like the maladaptive neural plasticity that contributes to somatosensory symptoms of chronic pain, concurrent maladaptive plasticity occurs in neural circuits that regulate motivation. Therefore, we focused on the nucleus accumbens core (NAc) because it is a key node of the neural circuits mediating motivated behaviors, and activity within the human NAc correlates with both the subjective experience of pain as well as the transition to chronic pain.

Chronic pain reduces motivation in two mouse models

We used two mouse models of chronic pain; chronic inflammatory pain in the hind paw and neuropathic pain induced by means of selective injury of the sciatic nerve (SNI). To measure motivation, we used a progressive ratio (PR) operant test in which it becomes progressively more difficult to earn each subsequent reward. The point at which the subject gives up provides a measure of motivation to work for reward.

Chronic pain elicits synaptic modifications in nucleus accumbens

To determine whether chronic pain elicits synaptic changes in NAc circuitry, we prepared brain slices from bacterial artificial chromosome (BAC) transgenic animals and made targeted whole-cell recordings from visually identified medium spiny neurons (MSNs) belonging to either the direct pathway, D1 dopamine receptor expressing MSNs (D1-MSNs), or the indirect pathway, D2 dopamine receptor expressing MSNs (D2-MSNs).

Chronic pain elicits synaptic modifications in nucleus accumbens

Galanin is required for pain-induced synaptic modifications in NAc

In several brain regions, activation of G protein–coupled receptors (GPCRs) by different neuromodulators causes changes in synaptic NMDAR stoichiometry. We investigated the possible role of the neuropeptide galanin (Gal) in the pain-induced changes in NMDAR stoichiometry in NAc D2-MSNs.

The results thus far suggest that during the onset of chronic pain, Gal in the NAc signals through GalR1 to increase the synaptic fraction of GluN2B in D2-MSNs. Then over the ensuing 1 to 2 weeks, AMPAR-mediated synaptic transmission progressively decreases. In other brain regions, a similar change in NMDAR stoichiometry has been suggested to reduce the threshold for induction of long-term depression (LTD) of AMPAR-mediated transmission.

Discussion

The NAc is a key node of the neural circuitry that regulates motivation.

Simple models proposing a dichotomous role for striatal indirect and direct pathways have been useful in generating hypotheses with which to describe the circuit adaptations underlying behaviors associated with models of addiction and depression. However, they are inadequate to account for the diverse actions of neuropeptides on NAc synaptic and circuit function as well as the neuronal activity observed during operant behaviors. Nonetheless, the present findings—along with the observations that reductions in effortful behavior are caused by blocking D2 receptors in NAc and that these effects can be reversed by A2a receptor antagonists -- support a key role of NAc D2-MSNs in regulating performance during more difficult tasks. Because the NAc integrates inputs from multiple structures, future studies will need to address the critical question of whether the chronic pain–induced synaptic changes are global, affecting all excitatory inputs onto MSNs, or rather are input-specific.

Previous studies on mouse models of chronic pain report no change in home cage behaviors or measures of affective behaviors during the first month of the pathology. Within a similar time frame, by focusing on a more subtle aspect of goal-directed operant behavior—the motivation to work for natural reward—we found that motivation was impaired. Our results suggest that pain-induced synaptic adaptations within the NAc contribute to a subjective impairment in the ability to initiate or sustain physical or mental tasks, or to the symptom of central fatigue commonly reported by chronic pain patients. These results also suggest specific synaptic targets that may be susceptible to therapeutic interventions.

[end of paraphrase]

Return to — Motivation