The control of tonic pain by active relief learning.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang S
PROVIDER: S-EPMC5843408 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
The control of tonic pain by active relief learning.
Zhang Suyi S Mano Hiroaki H Lee Michael M Yoshida Wako W Kawato Mitsuo M Robbins Trevor W TW Seymour Ben B
eLife 20180227
Tonic pain after injury characterises a behavioural state that prioritises recovery. Although generally suppressing cognition and attention, tonic pain needs to allow effective relief learning to reduce the cause of the pain. Here, we describe a central learning circuit that supports learning of relief and concurrently suppresses the level of ongoing pain. We used computational modelling of behavioural, physiological and neuroimaging data in two experiments in which subjects learned to terminate ...[more]
Similar Datasets
Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
2024-09-12 | GSE267265 | GEO
Project description:BackgroundEpidural analgesia offers greater pain relief compared to systemic opioid-based medications, but its effect on morbidity and mortality is unclear. This review was originally published in 2006 and was updated in 2012 and again in 2016.ObjectivesTo assess the benefits and harms of postoperative epidural analgesia in comparison with postoperative systemic opioid-based analgesia for adults undergoing elective abdominal aortic surgery.Search methodsIn the updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and five trial registers in November 2014, together with reference checking to identify additional studies.Selection criteriaWe included all randomized controlled trials comparing postoperative epidural analgesia and postoperative systemic opioid-based analgesia for adults who underwent elective open abdominal aortic surgery.Data collection and analysisTwo authors independently assessed trial quality and extracted data. We contacted study authors for additional information and data when required. We assessed the level of evidence according to the scale provided by the GRADE working group.Main resultsWe included 15 trials published from 1987 to 2009 with 1498 participants in this updated review. Participants had a mean age between 60.5 and 71.3 years. The percentage of women in the included studies varied from 0% to 28.1%. Adding an epidural to general anaesthesia for people undergoing abdominal aortic repair reduced myocardial infarction (risk ratio (RR) 0.54 (95% confidence interval (CI) 0.30 to 0.97); I(2) statistic = 0%; number needed to treat for one additional beneficial outcome (NNTB) 28 (95% CI 19 to 1423), visual or verbal analogical scale (VAS) scores up to three days after the surgery (mean difference (MD) -1.78 (95% CI -2.32 to -1.25); I(2) statistic = 0% for VAS scores on movement at postoperative day one), time to tracheal extubation (standardized mean difference (SMD) -0.42 (95% CI -0.70 to -0.15); I(2) statistic = 83%; equivalent to a mean reduction of 36 hours), postoperative respiratory failure (RR 0.69 (95% CI 0.56 to 0.85); I(2) statistic = 0%; NNTB 8 (95% CI 6 to 16)), gastrointestinal bleeding (OR 0.20 (95% CI 0.06 to 0.65); I(2) statistic = 0%; NNTB 32 (95% CI 27 to 74)) and time spent in the intensive care unit (SMD -0.23 (95% CI -0.41 to -0.06); I(2) statistic = 0%; equivalent to a mean reduction of six hours). We did not demonstrate a reduction in the mortality rate up to 30 days (RR 1.06 (95% CI 0.60 to 1.86); I(2) statistic = 0%). The level of evidence was low for mortality and time before tracheal extubation; moderate for myocardial infarction, respiratory failure and intensive care unit length of stay; and high for gastrointestinal bleeding and VAS scores.Authors' conclusionsEpidural analgesia provided better pain management, reduced myocardial infarction, time to tracheal extubation, postoperative respiratory failure, gastrointestinal bleeding, and intensive care unit length of stay compared with systemic opioid-based drugs. For mortality, we did not find a difference at 30 days.
| S-EPMC6464571 | biostudies-literature
Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
2024-09-12 | GSE267264 | GEO
Project description:Opioids remain the mainstay of severe pain management in patients with cancer. The hallmark of pain management is individualization of therapy. Although almost all clinically used drugs act through mu opioid receptors, they display subtle but important differences pharmacologically. Furthermore, not all patients respond equally well to all drugs. Evidence suggests that these variable responses among patients have a biologic basis and are likely to involve both biased agonism and the many mu opioid receptor subtypes that have been cloned.
| S-EPMC4031189 | biostudies-other
Project description:The interruptive effect of painful experimental stimulation on cognitive processes is a well-known phenomenon. This study investigated the influence of pain duration on the negative effects of pain on cognition. Thirty-four healthy volunteers performed a rapid serial visual presentation task (RSVP) in which subjects had to detect (visual detection task) and count the occurrence of a target letter (working memory task) in two separate sessions while being stimulated on the left volar forearm with either short (2 sec) or long (18 sec) painful heat stimuli of equal subjective intensity. The results show that subjects performed significantly worse in the long pain session as indexed by decreased detection and counting performance. Interestingly, this effect on performance was also observed during control trials of the long pain session in which participants did not receive any painful stimulation. Moreover, subjects expected long painful stimulation to have a greater impact on their performance and individual expectation correlated with working memory performance. These findings suggest that not only the length of painful stimulation but also its expected ability to impair cognitive functioning might influence the interruptive function of pain. The exact relevance of expectation for the detrimental effects of pain on cognitive processes needs to be explored in more detail in future studies.
| S-EPMC4335041 | biostudies-literature
Project description:Under physiological conditions, momentary pain serves vital protective functions. Ongoing pain in chronic pain states, on the other hand, is a pathological condition that causes widespread suffering and whose treatment remains unsatisfactory. The brain mechanisms of ongoing pain are largely unknown. In this study, we applied tonic painful heat stimuli of varying degree to healthy human subjects, obtained continuous pain ratings, and recorded electroencephalograms to relate ongoing pain to brain activity. Our results reveal that the subjective perception of tonic pain is selectively encoded by gamma oscillations in the medial prefrontal cortex. We further observed that the encoding of subjective pain intensity experienced by the participants differs fundamentally from that of objective stimulus intensity and from that of brief pain stimuli. These observations point to a role for gamma oscillations in the medial prefrontal cortex in ongoing, tonic pain and thereby extend current concepts of the brain mechanisms of pain to the clinically relevant state of ongoing pain. Furthermore, our approach might help to identify a brain marker of ongoing pain, which may prove useful for the diagnosis and therapy of chronic pain.
| S-EPMC4816790 | biostudies-literature
Project description:Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.
| S-EPMC3427725 | biostudies-literature
Project description:Dramatically up-regulated in the dorsal horn of the mammalian spinal cord following inflammation or nerve injury, neuropeptide Y (NPY) is poised to regulate the transmission of sensory signals. We found that doxycycline-induced conditional in vivo (Npy(tet/tet)) knockdown of NPY produced rapid, reversible, and repeatable increases in the intensity and duration of tactile and thermal hypersensitivity. Remarkably, when allowed to resolve for several weeks, behavioral hypersensitivity could be dramatically reinstated with NPY knockdown or intrathecal administration of Y1 or Y2 receptor antagonists. In addition, Y2 antagonism increased dorsal horn expression of Fos and phosphorylated form of extracellular signal-related kinase. Taken together, these data establish spinal NPY receptor systems as an endogenous braking mechanism that exerts a tonic, long-lasting, broad-spectrum inhibitory control of spinal nociceptive transmission, thus impeding the transition from acute to chronic pain. NPY and its receptors appear to be part of a mechanism whereby mammals naturally recover from the hyperalgesia associated with inflammation or nerve injury.
| S-EPMC3084123 | biostudies-literature
Project description:Postoperative pain relief in 40 children undergoing elective infraumbilical surgery was assessed after caudal epidural adminstration of either lignocaine or bupivacaine in the doses of 0.5 mL/kg body weight of a 1 per cent solution and 0.5 mL/kg body weight of a 0.25 per cent solution respectively. Pain free period was assessed by subjective pain scales. The pain free period was significantly prolonged in children who were given bupivacaine (14.75 ± 2.75 hours) as compared to lignocaine (7.25 ± 3.25 hours).
| S-EPMC5530789 | biostudies-other
Project description:ObjectivePhantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS-induced PLP relief is needed for future implementation of such treatment and generalization to related conditions.MethodsWe used a within-participants, double-blind, and sham-controlled design to alleviate PLP via task-concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation.ResultsA single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid- and posterior insula and secondary somatosensory cortex (S2).InterpretationThe observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid- and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task-concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. ANN NEUROL 2019;85:59-73.
| S-EPMC6492189 | biostudies-literature