Reward and motivation in pain and pain relief

Abstract

Pain is fundamentally unpleasant, a feature that protects the organism by promoting motivation and learning. Relief of aversive states, including pain, is rewarding. The aversiveness of pain, as well as the reward from relief of pain, is encoded by brain reward/motivational mesocorticolimbic circuitry. In this Review, we describe current knowledge of the impact of acute and chronic pain on reward/motivation circuits gained from preclinical models and from human neuroimaging. We highlight emerging clinical evidence suggesting that anatomical and functional changes in these circuits contribute to the transition from acute to chronic pain. We propose that assessing activity in these conserved circuits can offer new outcome measures for preclinical evaluation of analgesic efficacy to improve translation and speed drug discovery. We further suggest that targeting reward/motivation circuits may provide a path for normalizing the consequences of chronic pain to the brain, surpassing symptomatic management to promote recovery from chronic pain.

Figure 1

The corticolimbic circuit integrates motivationally salient information, including pain, and makes decisions about action selection. The NAc receives afferent nociceptive information through connections with the thalamus, parabrachial area (PB), amygdala (Amy) and ACC. Direct projections from the spinal cord to the NAc may be postulated on the basis of findings in rodents (red lines). VTA dopaminergic inputs to the NAc signal saliency, as well as the value of pain or relief. Corticostriatal connections from prefrontal, orbitofrontal and anterior cingulate cortices contribute to affective, emotional and cognitive control of pain perception and are involved in motivational decision-making. In the NAc, glutamatergic outputs from the amygdala converge on dopaminergic terminals from the VTA and influence motivated behavior in response to stress and anxiety (black lines). A descending pathway from the NAc that can modulate spinal nociceptive signals, possibly via the RVM, has been suggested (gold dotted line). Chronic pain states are characterized by anatomical and functional reorganization of the corticolimbic circuit, including changes in gray matter density in the PFC, ACC and NAc and increased functional connectivity between the PFC and NAc.

Figure 2

Relief of ongoing pain produces CPP. Left, CPP box. Right, in rats with incision of the hindpaw peripheral nerve blockade of the injured limb with popliteal fossa lidocaine produced CPP at 1 d but not 4 d after incision, indicating time-dependent resolution of ongoing postsurgical pain. Data are means ± s.e.m. *P < 0.05; Student’s paired t-test. Right panel adapted from ref. .

Figure 3

Pain relief produces CPP through activation of mesolimbic reward/motivation circuitry. In rats with ongoing postincisional pain, peripheral nerve blockade of the injured limb with popliteal fossa lidocaine resulted in the activation of FOS in dopaminergic (tyrosine hydroxylase positive; DA) neurons in the VTA (top left; FOS, green; tyrosine hydroxylase, red) and release of dopamine in the NAc measured by in vivo microdialysis (bottom left; area under the time curve (AUC) of percentage change in dopamine). In incised rats at 1 day after surgery, CPP to peripheral nerve blockade (Fig. 1) was prevented by inactivation of dopaminergic neurons in the VTA with the GABA_B receptor agonist baclofen (top right). Inhibition of dopamine neurotransmission in the NAc by the dopamine receptor antagonist flupenthixol also prevented CPP in rats 1 d after incision surgery Student’s paired t-test. Data are means ± s.e.m. Adapted from ref. .