Brain Circuits Encoding Reward from Pain Relief

Navratilova, Edita; Atcherley, Christopher W.; Porreca, Frank

doi:10.1016/j.tins.2015.09.003

Cited by 178 publications

(151 citation statements)

References 86 publications

(101 reference statements)

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“…Withdrawal-induced changes in brain reward deficits (Kenny et al, 2006) and enhancement of opioid-seeking behavior (Lenoir and Ahmed, 2007) are manifest in opioid-dependent animals, and may correspond with altered pain sensitivity. Chronic pain causes sustained emotional distress, while relief from pain is rewarding (King et al, 2009; Navratilova et al, 2015), and these relationships may drive the long-lasting addictive potential of opioid medications in pain-sensitive individuals (Ren et al, 2009). Our molecular findings within central motivation circuitry support previous evidence suggesting that negative affective states associated with opioid withdrawal may promote escalation of drug intake to alleviate pain (Hipólito et al, 2015; Taylor et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

et al. 2017

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Repeated use of opioids can lead to the development of analgesic tolerance and dependence. Additionally, chronic opioid exposure can cause a paradoxical emergence of heightened pain sensitivity to noxious stimuli, termed hyperalgesia, which may drive continued or escalated use of opioids to manage worsening pain symptoms. Opioid-induced hyperalgesia has traditionally been measured in rodents via reflex-based assays, including the von Frey method. To better model the cognitive/motivational dimension of pain in a state of opioid dependence and withdrawal, we employed a recently developed non-reflex-based method for measuring pain avoidance-like behavior in animals (mechanical conflict avoidance test). Adult male Wistar rats were administered an escalating dose regimen of morphine (opioid-dependent group) or repeated saline (control group). Morphine-dependent rats exhibited significantly greater avoidance of noxious stimuli during withdrawal. We next investigated individual relationships between pain avoidance-like behavior and alterations in protein phosphorylation in central motivation-related brain areas. We discovered that pain avoidance-like behavior was significantly correlated with alterations in phosphorylation status of protein kinases (ERK, CaMKII), transcription factors (CREB), presynaptic markers of neurotransmitter release (Synapsin), and the rate-limiting enzyme for dopamine synthesis (TH) across specific brain regions. Our findings suggest that alterations in phosphorylation events in specific brain centers may support cognitive/motivational responses to avoid pain.

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Section: Discussionmentioning

confidence: 99%

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

et al. 2017

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“…The well-known dual analgesic/ rewarding effects of morphine and the behavioral phenotypes of Oprm1 −/− mutant mice showing increased pain perception (36) and reduced drug (37) or social (38,39) reward, posit MOR as a central player for these fundamental processes. Indeed, two decades of Oprm1 −/− mouse studies have unambiguously established the pivotal role of MOR in both pain and pleasure (Dataset S1 and references therein), recognized as intermingled processes at circuit level (40) and for pathology (41). In our analysis, the major influence of Oprm1 inactivation on aversion/pain-related, rather than reward connectivity, may reflect a stronger inhibitory MOR tone or developmental influence on negative affect centers, at least under resting-state conditions.…”

Section: Discussionmentioning

confidence: 99%

“…From an evolutionary perspective, pain represents a key signal for survival, and successful coping with a pain stimulus is essential to gain a selective advantage (42). Despite the antique notion that pain and pleasure form a continuum, it is only recently that the rewarding value of pain relief has been recognized (40,41). The key implication of MOR activity in dampening physical, emotional, and social pain, evidenced in human PET imaging studies (see ref.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

Mechling

Arefin

Lee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Connectome genetics seeks to uncover how genetic factors shape brain functional connectivity; however, the causal impact of a single gene's activity on whole-brain networks remains unknown. We tested whether the sole targeted deletion of the mu opioid receptor gene (Oprm1) alters the brain connectome in living mice. Hypothesis-free analysis of combined resting-state fMRI diffusion tractography showed pronounced modifications of functional connectivity with only minor changes in structural pathways. Fine-grained resting-state fMRI mapping, graph theory, and intergroup comparison revealed Oprm1-specific hubs and captured a unique Oprm1 gene-to-network signature. Strongest perturbations occurred in connectional patterns of pain/aversion-related nodes, including the mu receptor-enriched habenula node. Our data demonstrate that the main receptor for morphine predominantly shapes the so-called reward/aversion circuitry, with major influence on negative affect centers. mouse brain connectivity | resting-state functional MRI | diffusion tensor imaging | mu opioid receptor | reward/aversion network N euronal connectivity is at the foundation of brain function (1) and the concept that brain connectivity patterns are dynamically shaped by experience, pathology, and genetics has gained increasing importance. In humans, MRI has opened the era of connectome/imaging genetics to elucidate how genetic factors affect brain organization and connectivity in healthy individuals and disease, and to correlate genotype to phenotype (2). However, the causal impact of a single gene on overall functional connectivity (FC) remains largely unknown, and animal research is best suited to this goal. Here we tested whether combined functional/structural MRI in live animals (3-8) coupled to open-ended postprocessing analysis would reveal connectivity alterations upon targeted inactivation of a single gene. The mu opioid receptor (MOR) mediates the remarkably potent analgesic and addictive properties of opiates, like morphine (9), and belongs to the endogenous opioid system that controls sensory, emotional, and cognitive processes. This receptor is broadly distributed throughout the nervous system (10). It is a key component to facilitate reward (11) and relieves the negative experience of pain (12)(13)(14). In this report we show that targeted deletion of the MOR gene (Oprm1) significantly alters the brain connectome in living mice and predominantly reshapes the so-called reward/aversion network involved in pain, depression, and suicide (15). Results and DiscussionFine-Grained Mapping of the Mouse Brain Functional Connectome. In a first step, we established fine-grained mapping of the mouse brain functional connectome (MBFC) in control and Oprm1 −/− living mice. Using data-driven spatial independent component analysis (100-ICASSO) (4) of combined blood oxygenation level-dependent (BOLD) resting-state functional MRI (rsfMRI) datasets (Materials and Methods, Data Analysis), we identified 87 functional components, the patterns of which covered neur...

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“…Aversive to pain stimuli mainly is encoded by brain reward/motivational mesocorticolimbic circuitry [15].…”

Section: Tail Flick Test Groups Latency To Withdraw the Tail (S)mentioning

confidence: 99%

Reduction of Neurogenesis with Social Isolation Decreases Pain Sensitivity in Tail Flick Test in Male Rats

Famitafreshi¹,

Karimian²

2017

WJNS

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Introduction: Pain is a complex phenomenon and in many diseases is the cardinal manifestation. In many of them, the source of pain is obscure and in turn curing pain also becomes difficult. Finding a new regulatory mechanism for pain perception and processing such as alternation of neurogenesis may establish a new treatment. Methods and Materials: In this study, 32 male Sprague-Dawley rats were randomly divided into four groups: social, isolated, morphine-treated socialized (MTS) and morphine-treated isolated (MTI). After injection of BrdU for 14 days (50 mg/kg/rat/day/i.p) and morphine for seven days from day 8 (3 mg/kg/rat/day/i.p), rats were performed tail flick test and then sacrificed. Brains were prepared for assessing neurogenesis and serums were collected for assessing glutathione. Results: In tail flick test isolated and morphine-treated isolated rats had decreased sensitivity to pain stimuli compared to social and morphine-treated socialized rats, respectively. In assessing neurogenesis, isolated and morphinetreated isolated rats had reduced numbers of newly generated neurons compared to social and morphine-treated socialized rats, respectively. Glutathione in serum in isolated and morphine-treated isolated rats increased compared to social and morphine-treated socialized rats, respectively. Conclusion: Reduction of neurogenesis was associated with reduced pain sensitivity in isolated groups. So, isolation may alleviate pain and reduce pain threshold and sensitivity.

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Brain Circuits Encoding Reward from Pain Relief

Cited by 178 publications

References 86 publications

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

Neurobiological Correlates of Pain Avoidance-Like Behavior in Morphine-Dependent and Non-Dependent Rats

Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

Reduction of Neurogenesis with Social Isolation Decreases Pain Sensitivity in Tail Flick Test in Male Rats

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