Pain relief produces negative reinforcement through activation of mesolimbic reward–valuation circuitry

Abstract

Relief of pain is rewarding. Using a model of experimental postsurgical pain we show that blockade of afferent input from the injury with local anesthetic elicits conditioned place preference, activates ventral tegmental dopaminergic cells, and increases dopamine release in the nucleus accumbens. Importantly, place preference is associated with increased activity in midbrain dopaminergic neurons and blocked by dopamine antagonists injected into the nucleus accumbens. The data directly support the hypothesis that relief of pain produces negative reinforcement through activation of the mesolimbic reward-valuation circuitry.motivated behavior | incision | in vivo microdialysis | immunohistochemistry | ventral tegmental area R einforcement of behaviors that maximize benefit (positive reinforcement) and reduce loss or injury (negative reinforcement) is crucial for survival. Whereas positive reinforcement can be produced by activation of mesolimbic dopaminergic pathways, the neural circuits that underlie negative reinforcement are not well understood. Ongoing pain can be "unmasked" in animals using conditioned place preference (CPP). Thus, in the presence of ongoing pain, pairing manipulations that are not rewarding in the absence of pain, such as peripheral nerve block (PNB) or intrathecal administration of ω-conotoxin or clonidine, with a previously neutral context elicits CPP (1-3). CPP resulting from pain relief is a measure of negative reinforcement.Human functional imaging studies have shown that offset of an acute noxious stimulus (4, 5) or placebo analgesia (6) activates brain regions that overlap extensively with those implicated in appetitive rewards, in particular the ventral tegmental area (VTA), and its dopaminergic projections to the nucleus accumbens (NAc) (5, 6). Manipulations that disrupt mesolimbic dopamine transmission attenuate food or drug reward-induced CPP (7,8). Electrophysiological recordings from dopaminergic neurons in the VTA demonstrate phasic neuronal activation by primary food or liquid rewards, by rewarding drugs, and reward-predicting cues (9). Similarly, immunohistochemical studies show increased expression of the immediate early gene cFOS in the VTA in response to rewarding drugs, providing further support for an enhanced neuronal activity (10-13). The NAc can be anatomically and functionally divided into core and shell regions that respectively receive projections from the lateral and medial VTA (14). In vivo microdialysis measurements or fast-scan voltammetry demonstrate that appetitive rewards promote an efflux of dopamine in the NAc (15, 16). It has been suggested that NAc neurons signal reward value and participate in behavioral decision making (17-21).We hypothesized that relief of ongoing pain would activate the mesolimbic dopamine pathway and that such activation is necessary for negative reinforcement. We tested this hypothesis directly in rats with incisional injury-induced pain (22) subsequently relieved by peripheral nerve block. ResultsIncision of the skin and underlying...

Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats

“…The results presented might thus be explained by a capsaicin-induced enhancement of thermal gating of TRPV1 expressed in polymodal nociceptors mediating thermal pain sensation (Carstens et al, 2007;Albin et al, 2008). However, we do not exclude the possibility that, in the two-temperature preference tests, the rats prefer the cool side because they are seeking alleviation of the 'burning' pain (De Felice et al, 2013;Navratilova et al, 2012Navratilova et al, , 2013) that can be specified on the modulation of TRP channel sensitivity. Hoffmann et al (2013) have recently shown that TRPA1 and TRPV1 channels contribute to thermal nociception, and that both TRPA1 and TRPV1 null mice presented behavioral deficits in heat sensitivity.…”

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

“…This is the first study to report a pain-related and analgesic-reversible decrease in microdialysis measures of NAc DA after treatment with a noxious stimulus. However, two other recent studies reported increases in NAc DA release after antinociceptive treatments in rat models of postsurgical or cephalic pain (De Felice et al, 2013;Navratilova et al, 2013). This preclinical evidence for reciprocal effects of pain-and analgesia-related manipulations on NAc DA corresponds to clinical evidence from functional magnetic resonance imaging studies for reciprocal negative/positive signals in NAc at pain onset/offset, respectively (Becerra and Borsook, 2008).…”

Pain-relief learning in flies, rats, and man: basic research and applied perspectives

“…This suggests that also in rats changes in the relative timing of cue and punishment do more than affecting whether and how much learning occurs, but rather can affect the valence of the respective mnemonic effect (for a related finding see also Smith and Buchanan 1954). A different approach was used by Navratilova et al (2012): The authors investigated tonic post-surgical pain and induced relief by pharmacological treatment of that pain. Using a place preference/avoidance apparatus, such treatment was paired with one compartment of the apparatus whereas the other compartment was paired with a placebo treatment.…”

“…1) (we use "relief" to refer specifically to the acute effects of punishment offset; an equally legitimate yet broader use of the word in, e.g., "fear relief," encompasses any process that eases fear [Riebe et al 2012]). Indeed, in experimental settings, it turns out that stimuli experienced before and during a punishing episode are later avoided as they signal upcoming punishment, whereas stimuli experienced after a painful episode can subsequently prompt approach behavior, arguably (Box 1) because of their association with the relieving cessation of pain (Konorski 1948;Smith and Buchanan 1954;Wolpe and Lazarus 1966;Zanna et al 1970;Solomon and Corbit 1974;Schull 1979;Solomon 1980;Wagner 1981;Walasek et al 1995;Tanimoto et al 2004;Yarali et al 2008Yarali et al , 2009bAndreatta et al 2010Andreatta et al , 2012Yarali and Gerber 2010;Ilango et al 2012;Navratilova et al 2012;Diegelmann et al 2013b); for a corresponding finding in the appetitive domain, see Hellstern et al (1998) and Felsenberg et al (2013). Such relief can both support the learning of the cues associated with the disappearance of the threat and reinforce those behaviors that helped to escape it.…”