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Brain Circuits Encoding Reward from Pain Relief

2015; Elsevier BV; Volume: 38; Issue: 11 Linguagem: Inglês

10.1016/j.tins.2015.09.003

1878-108X

Edita Navratilova, Christopher W. Atcherley, Frank Porreca,

Receptor Mechanisms and Signaling

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. 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. 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. an operant learning paradigm used to evaluate the motivational effects of different experiences in laboratory animals. Typically, animals are conditioned to associate two different treatments (usually control and test treatment) with two conditioning chambers distinguished by sensory cues. Animals are then given access to both chambers and the time spent within each chamber is recorded and analyzed for chamber preference. The paradigm can be used in animals with ongoing pain to investigate the efficacy of analgesics in alleviating the aversive aspects of pain. an electroanalytical method that enables real-time measurements of chemical activity. Modern in vivo FSCV involves applying a triangle waveform to monitor the oxidation and reduction of neurotransmitters absorbed to the surface of a carbon-fiber microelectrode (CFME) [81Wightman R.M. Detection technologies. Probing cellular chemistry in biological systems with microelectrodes.Science. 2006; 311: 1570Crossref PubMed Scopus (361) Google Scholar]. This highly sensitive and selective technique has been successfully used to measure rapid, subsecond changes of dopamine concentrations in the extracellular space in response to various pharmacological and behavioral stimuli. related to a pleasant or rewarding feeling. a stimulus that is damaging or has the potential to damage tissues. Noxious mechanical, thermal, or chemical stimuli are detected by specialized nerve endings called nociceptors and transduced from the site of injury via these peripheral nerves to the spinal cord and the brain. This neural process, termed nociception, triggers various reflexive and autonomic responses and can result in the subjective experience of pain. Pain comprises sensory, affective, and cognitive aspects. Affective or emotional features of pain motivate behavior. injury typically results in hypersensitivity to evoked mechanical or thermal stimuli and ongoing (or ‘spontaneous’) pain that is present without an apparent external stimulation. Although evoked hypersensitivity is a problem in some patients, aversive (i.e., affective) features of ongoing pain are most bothersome. Affective features of pain are tightly linked to sensory input [3Fields H.L. Pain: an unpleasant topic.Pain. 1999; 6: S61Abstract Full Text PDF PubMed Scopus (142) Google Scholar]; however, modulation of pain affect can be achieved without altering nociceptive input suggesting that the affective and sensory qualities of pain are partially separable. Relief of pain aversiveness is sufficient to relieve ‘pain’ perception. In nonverbal animals, relief of aversiveness of ongoing pain can be inferred from motivated behavior (CPP). a functional imaging technique that detects gamma rays emitted from a positron-emitting radionuclide. Radionuclide-containing molecules (radiotracers) that bind to specific receptors in the brain, such as dopamine and opioid receptors, have been used to investigate the release and binding of endogenous neurotransmitters to these receptors. As the endogenous neurotransmitters are released, they compete for the receptor binding sites and displace the radiotracer. Thus, reduced radiotracer binding is usually interpreted as increased release of the endogenous ligand.