Brain Circuits Encoding Reward from Pain Relief

doi:10.1016/j.tins.2015.09.003

Trends in Neurosciences

Volume 38, Issue 11, November 2015, Pages 741-750

https://doi.org/10.1016/j.tins.2015.09.003 Get rights and content

Trends

Electrophysiological studies in rats demonstrate that a subset of mesolimbic dopamine neurons that are initially inhibited by a noxious stimulation show ‘rebound’ excitation at the offset of the stimulus.

Recent investigations using fast-scan cyclic voltammetry in rats show phasic dopamine release in the nucleus accumbens shell at the termination of a noxious tail pinch.

Using neuroimaging in humans and rats, increased BOLD activity was detected at the offset of a brief noxious stimulus in the nucleus accumbens and in the anterior cingulate cortex.

In Drosophila, rodents, and humans, relief of an acute painful stimulus is associated with conditioned reward learning.

In rats, relief of ongoing pain promotes a conditioned place preference that requires opioid signaling in the anterior cingulate cortex and subsequent release of dopamine in the nucleus accumbens.

Relief from pain in humans is rewarding and pleasurable. Primary rewards, or reward-predictive cues, are encoded in brain reward/motivational circuits. While considerable advances have been made in our understanding of reward circuits underlying positive reinforcement, less is known about the circuits underlying the hedonic and reinforcing actions of pain relief. We review findings from electrophysiological, neuroimaging, and behavioral studies supporting the concept that the rewarding effect of pain relief requires opioid signaling in the anterior cingulate cortex (ACC), activation of midbrain dopamine neurons, and the release of dopamine in the nucleus accumbens (NAc). Understanding of circuits that govern the reward of pain relief may allow the discovery of more effective and satisfying therapies for patients with acute or chronic pain.

Section snippets

Relief of Pain Is a Reward

Substantial scientific progress in the past century has deepened our understanding of somatosensation, including the neurobiology of pain that often follows from activation of nociceptors 1, 2. Pain is commonly categorized along with other sensations and relief of pain is thus often interpreted simply as termination of nociceptive transmission. Early Greek philosophers, however, grouped pain with emotions and appetites rather than sensation. Pain was considered to be the opposite of pleasure [3]

Mesolimbic Dopaminergic Responses to the Onset and Offset of Pain

Mesolimbic dopamine neurons are well recognized for their responses to primary rewards and reward-predicting cues, as well as for their role in approach behavior, learning, reinforcement, decision making, and the expression of positive emotions such as pleasure and happiness (reviewed in 13, 14, 15). Electrophysiological characterization of midbrain dopamine neurons in monkeys and rodents has established that, in addition to tonic neural activity, most neurons display phasic activations

Brain Activity in Response to Pain and Pain Relief

Major advances in elucidating the brain mechanisms of pain have been achieved using neuroimaging techniques in humans and animals. BOLD fMRI studies identified brain regions frequently activated by acute noxious stimulation, including the thalamus, the primary and secondary somatosensory cortices (S1, S2), the mid/posterior insula, and the ACC [36]. These regions interact with a broad network of corticolimbic structures encoding reward/motivation-related information to shape behavioral

Role of Endogenous Opioid Circuits in Pain and Pain Relief

Earlier studies with opioid antagonists established a critical role of the endogenous opioid system for innate analgesia during traumatic and stressful situations and during ‘runner's high’ 52, 53. ACC neurons express high levels of endogenous opioid neuropeptides and their receptors [54], suggesting that at least part of the endogenous analgesic effects could be mediated by opioid activity in this region [55]. Interestingly, in rats systemic administration of morphine is able to inhibit

Relief of Pain Provides a Motivational and Learning Signal

A series of studies conducted in Drosophila, rodents, and humans was implemented to investigate the mechanisms of learning associated with the relief of pain (reviewed in [59]). To assess both fear and relief conditioning, these studies used a paradigm in which a conditioning stimulus either preceded or followed a brief noxious electric shock, respectively. In Drosophila, when a neutral olfactory cue preceded the foot shock (fear conditioning), the odor acquired aversive conditioned valence.

NAc Dopamine Signaling and Relief of Ongoing Pain

The pain-relief signals discussed above have employed paradigms involving the rapid offset of an acute noxious stimulus. Given the known reorganization of brain circuits in chronic pain, it is important to determine whether relief of ongoing or chronic pain analogously produces a motivationally salient pain-relief signal and how this signal is mediated. This was investigated in rodent models of ongoing or chronic pain using the conditioned place preference (CPP) learning paradigm. Relief of

Opioid Signaling in the ACC and Relief of Ongoing Pain

Because endogenous as well as administered opioids are able to inhibit nociceptive neurons in the ACC, it is plausible to speculate that opioid activity in this region may be involved in relief of pain aversiveness and activation of the reward circuit. LaGraize et al. have demonstrated that, in neuropathic rats, microinjection of morphine into the ACC produced a selective decrease of affective/motivational aspects of pain with no alteration of the mechanical paw-withdrawal threshold [76].

Concluding Remarks: Brain Circuits for Pain-Relief Reward

In addition to nociceptive (sensory) information, the pain experience is significantly dependent on emotional and cognitive processing in the brain [50]. Onset of pain or increasing pain is a motivationally salient event that often supersedes other, competing motivational conditions to generate an appropriate behavioral response (e.g., avoidance, guarding, decreased mobility) [78]. Likewise, pain offset or reducing pain is also a motivationally relevant event leading to approach behavior. Thus,

Acknowledgments

The authors thank Professor Howard Fields, UCSF for helpful comments on the manuscript and the support of the NIDA (DA 034975).

Glossary

Blood oxygen level-dependent (BOLD) imaging: a technique used in fMRI that measures neuronal activity in different areas of the brain based on changes in the ratio of oxygenated to deoxygenated hemoglobin. In research, the method is used to determine which regions of the brain are activated during a specific task such as during the application of a painful stimulus.
Conditioned place preference (CPP): an operant learning paradigm used to evaluate the motivational effects of different experiences in

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Trends in Neurosciences

ReviewBrain Circuits Encoding Reward from Pain Relief

Trends

Section snippets

Relief of Pain Is a Reward

Mesolimbic Dopaminergic Responses to the Onset and Offset of Pain

Brain Activity in Response to Pain and Pain Relief

Role of Endogenous Opioid Circuits in Pain and Pain Relief

Relief of Pain Provides a Motivational and Learning Signal

NAc Dopamine Signaling and Relief of Ongoing Pain

Opioid Signaling in the ACC and Relief of Ongoing Pain

Concluding Remarks: Brain Circuits for Pain-Relief Reward

Acknowledgments

Glossary

Neuron

Cell

Pain

J. Pain

Neuron

Curr. Opin. Neurobiol.

Neuropharmacology

Trends Neurosci.

Brain Res. Rev.

Neuroscience

Trends Neurosci.

Neuropsychopharmacology

Biol. Psychiatry

Neuroscience

Pain

Neuron

Eur. J. Pain

Neuron

Pain

Eur. J. Pain

Neuron

Brain Res.

Neuroimage

Pain

Pain

J. Pain

J. Pain

Neurosci. Lett.

Pain

Pain

Exp. Neurol.

Neuron

Behav. Brain Res.

Pain relief as an opponent process: a psychophysical investigation

Eur. J. Neurosci.

Relief as a reward: hedonic and neural responses to safety from pain

PLoS ONE

Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function

J. Neurosci.

Fibromyalgia patients show an abnormal dopamine response to pain

Eur. J. Neurosci.

Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain

Br. J. Pharmacol.

Predicting transition to chronic pain

Curr. Opin. Neurol.

Chronic back pain is associated with alterations in dopamine neurotransmission in the ventral striatum

J. Neurosci.

Reward and motivation in pain and pain relief

Nat. Neurosci.

Two types of dopamine neuron distinctly convey positive and negative motivational signals

Nature

Duration of inhibition of ventral tegmental area dopamine neurons encodes a level of conditioned fear

J. Neurosci.

Neuron-type-specific signals for reward and punishment in the ventral tegmental area

Nature

Review
Brain Circuits Encoding Reward from Pain Relief