AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfuncti...AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. METHODS： Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities （visual analogue scale, VAS 0-100） during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously （heterotopic stimulation） were recorded in 40 female patients with IBS and 20 female healthy controls. RESULTS： Rectal hypersensitivity （defined by 95% Cl of controls） was seen in 21 （53%）, somatic hypersensitivity in 22 （55%） and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 （-11 to -1） in controls, but increased rectal pain by 2 （-3 to ＋6） in all IBS patients （P 〈 0.05） and by 8 （-2 to ＋19） in IBS patients with somatic and visceral hypersensitivity （P 〈 0.02）. CONCLUSION： A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.展开更多
Pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the p...Pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the periphery,spinal cord,and brain.The pathogenesis of chronic pain is still not fully understood,which makes the clinical treatment challenging.Optogenetics,which combines optical and genetic technologies,can precisely intervene in the activity of specific groups of neurons and elements of the related circuits.Taking advantage of optogenetics,researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission,pain modulation,and chronic pain both in the periphery and the central nervous system.In this review,we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.展开更多
The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain...The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain perception.Despite extensive research efforts to unravel its mechanisms,the operational intricacies of SRD remain poorly understood.Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders.This comprehensive review aims to analyze 36 years(1989–2024)of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control(DNIC),also known as conditioned pain modulation(CPM)in humans,and its interconnected neural circuits.Moreover,this review explores the neural circuits related to SRD,including locus coeruleus(LC)-SRD,parabrachial nucleus(PBN)-SRD,rostroventromedial medulla(RVM)-ventrolateral medulla(VLM)-SRD,anterior cingulate cortex(ACC)-SRD,medial medullary reticular formation(mMRF)-SRD,and dorsal striatum(DS)-SRD.Their activation also plays a significant role in analgesia.The pivotal roles of neurotransmitters such asμ-opioid receptor(MOR),noradrenaline,and metabotropic glutamate receptor 7(mGluR7)in modulating SRD responsiveness to pain stimuli are also discussed,as are the influences of SRD on different pain types.This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.展开更多
Background Pain sensitivity is critical for preventing non-suicidal self-injury(NSSI)behaviours;however,individuals engaging in such behaviours often exhibit decreased pain sensitivity,which may undermine this natural...Background Pain sensitivity is critical for preventing non-suicidal self-injury(NSSI)behaviours;however,individuals engaging in such behaviours often exhibit decreased pain sensitivity,which may undermine this natural safeguard.The dorsolateral prefrontal cortex(DLPFC)is a key region involved in pain regulation,and recent approaches using transcranial direct current stimulation(tDCS)to target the DLPFC have shown potential for modulating pain processing and restoring normal pain perception for individuals engaging in NSSI behaviours.Aims This study aimed to explore the immediate and short-term effects of a single session of tDCS on pain sensitivity in individuals with NSSI,as well as its secondary effects on mood and NSSI-related factors.Methods In this randomised,double-blind,parallel,sham-controlled clinical trial,participants with a history of NSSI were randomly assigned to receive either active or sham tDCS.The intervention consisted of a single 20 min tDCS session targeting the left DLPFC.The primary outcome was pain sensitivity,measured by the pressure pain threshold(PPT)and heat pain score(HPS).Secondary and additional outcomes included NSSI urges,NSSI resistance,self-efficacy in resisting NSSI,mood-related variables and exploratory cognitive-affective processes such as rumination,self-criticism and self-perceived pain sensitivity,assessed at baseline,immediately post-intervention,and at 24 hours,1 week and 2 weeks follow-ups.Results For the primary outcomes,no significant differences between groups were observed for pain sensitivity(PPT,padj=0.812;HPS,padj=0.608).However,an exploratory sensitivity analysis treating each trial as an individual observation revealed a significant effect on HPS(padj=0.036).For the secondary and additional outcomes,although there were initial improvements in joyful feelings and reductions in negative affect at 2 weeks post-intervention,these effects did not remain significant after multiple comparison corrections.Notably,reductions in rumination were statistically significant at both 1-week and 2-week follow-ups(1 week,p_(adj)=0.040;2 weeks,p_(adj)=0.042).There were no significant effects on NSSI urges,NSSI resistance,self-efficacy in resisting NSSI or self-criticism.Conclusions A single session of tDCS over the left DLPFC did not produce significant changes in pain sensitivity in individuals with NSSI.A sensitivity analysis indicated an effect on heat pain sensitivity,possibly reflecting changes in brain activity,warranting confirmation through neuroimaging.These findings suggest that tDCS warrants further investigation for its potential to influence pain-related cognitive-affective processes in individuals with NSSI.展开更多
Pain perception and its genesis in the human brain have been reviewed recently. In the current article, the reports on pain modulation in the human brain were reviewed from higher cortical regulation, i.e. top-down ef...Pain perception and its genesis in the human brain have been reviewed recently. In the current article, the reports on pain modulation in the human brain were reviewed from higher cortical regulation, i.e. top-down effect, particularly studied in psychological determinants. Pain modulation can be examined by gene therapy, physical modulation, pharmacological modulation, psychological modulation, and pathophysiological modulation. In psychological modulation, this article exam- ined （a） willed determination, （b） distraction, （c） placebo, （d） hypnosis, （e） meditation, （f） qi-gong, （g） belief, and （h） emotions, respectively, in the brain function for pain modulation. In each, the operational definition, cortical processing, neuroimaging, and pain modulation were systematically deliberated. However, not all studies had featured the brain modulation processing but rather demonstrated potential effects on human pain. In our own studies on the emotional modulation on human pain, we observed that emotions could be induced from music melodies or pictures perception for reduction of tonic human pain, mainly in potentiation of the posterior alpha EEG fields, likely resulted from underneath activities of precuneous in regulation of consciousness, including pain perception. To sum, higher brain functions become the leading edge research in all sciences. How to solve the information bit of thinking and feeling in the brain can be the greatest challenge of human intelligence. Application of higher cortical modulation of human pain and suffering can lead to the progress of social humanity and civilization.展开更多
Spinal cord injury （SCI） currently ranks second after mental retarda- tion among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neu...Spinal cord injury （SCI） currently ranks second after mental retarda- tion among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissues （Yezierski, 2005; D＇Angelo et al., 2013）.展开更多
Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the corre...Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.展开更多
Protein kinase D （PKD） is an evolutionarily-conserved family of protein kinases. It has structural, regulatory, and enzymatic properties quite different from the PKC family. Many stimuli induce PKD signaling, includ...Protein kinase D （PKD） is an evolutionarily-conserved family of protein kinases. It has structural, regulatory, and enzymatic properties quite different from the PKC family. Many stimuli induce PKD signaling, including G-protein-coupled receptor agonists and growth factors. PKD1 is the most studied member of the family. It functions during cell proliferation, differentiation, secretion, cardiac hypertrophy, immune regulation, angiogenesis, and cancer. Previously, we found that PKD1 is also critically involved in pain modulation. Since then, a series of studies performed in our lab and by other groups have shown that PKDs also participate in other processes in the nervous system including neuronal polarity establishment, neuroprotection, and learning. Here, we discuss the connections between PKD structure, enzyme function, and localization, and summarize the recent findings on the roles of PKD-mediated signaling in the nervous system.展开更多
Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （...Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.展开更多
A remarkable study by Guo et al.,published in Cell,suggests a compelling new direction for improving pain management:biased allosteric modulation of the neurotensin receptor 1(NTSR1),using the drug-like molecule SBI-8...A remarkable study by Guo et al.,published in Cell,suggests a compelling new direction for improving pain management:biased allosteric modulation of the neurotensin receptor 1(NTSR1),using the drug-like molecule SBI-810,promotesβ-arrestin2(βarr2)recruitment while avoiding canonical G protein signaling–thereby providing robust analgesia across a plethora of rodent models of both acute and chronic pain without impairing motor function,cognition,or causing opioid-like dependency.1,2 SBI-810 is introduced as a highly promising molecule underscoring the therapeutic potential of biased and allosteric G protein-coupled receptor(GPCR)ligands to address an urgent unmet medical need.展开更多
基金the Brain-Gut Research Group, Berne, Switzerland
文摘AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. METHODS： Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities （visual analogue scale, VAS 0-100） during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously （heterotopic stimulation） were recorded in 40 female patients with IBS and 20 female healthy controls. RESULTS： Rectal hypersensitivity （defined by 95% Cl of controls） was seen in 21 （53%）, somatic hypersensitivity in 22 （55%） and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 （-11 to -1） in controls, but increased rectal pain by 2 （-3 to ＋6） in all IBS patients （P 〈 0.05） and by 8 （-2 to ＋19） in IBS patients with somatic and visceral hypersensitivity （P 〈 0.02）. CONCLUSION： A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.
基金supported by grants from the National Natural Science Foundation of China(82073819 and 81872843)Fundamental Research Funds for the Central Universities of China(2021QNA7005).
文摘Pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the periphery,spinal cord,and brain.The pathogenesis of chronic pain is still not fully understood,which makes the clinical treatment challenging.Optogenetics,which combines optical and genetic technologies,can precisely intervene in the activity of specific groups of neurons and elements of the related circuits.Taking advantage of optogenetics,researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission,pain modulation,and chronic pain both in the periphery and the central nervous system.In this review,we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.
基金funded by the Key Program of the National Natural Science Foundation of China(No.82130122).
文摘The subnucleus reticularis dorsalis(SRD),also known as the dorsal reticular nucleus(DRt)or dorsal medullary reticular nucleus(MdD),which resides at the caudal end of the medulla,plays a pivotal role in regulating pain perception.Despite extensive research efforts to unravel its mechanisms,the operational intricacies of SRD remain poorly understood.Advances in experimental methodologies such as brain imaging and chemogenetics have facilitated deeper investigations into the involvement of SRD in various pain disorders.This comprehensive review aims to analyze 36 years(1989–2024)of preclinical research highlighting the critical role of SRD in diffuse noxious inhibitory control(DNIC),also known as conditioned pain modulation(CPM)in humans,and its interconnected neural circuits.Moreover,this review explores the neural circuits related to SRD,including locus coeruleus(LC)-SRD,parabrachial nucleus(PBN)-SRD,rostroventromedial medulla(RVM)-ventrolateral medulla(VLM)-SRD,anterior cingulate cortex(ACC)-SRD,medial medullary reticular formation(mMRF)-SRD,and dorsal striatum(DS)-SRD.Their activation also plays a significant role in analgesia.The pivotal roles of neurotransmitters such asμ-opioid receptor(MOR),noradrenaline,and metabotropic glutamate receptor 7(mGluR7)in modulating SRD responsiveness to pain stimuli are also discussed,as are the influences of SRD on different pain types.This review identified promising avenues for innovative analgesic treatments by shedding light on potential therapeutic strategies targeting SRD.
基金supported by National Natural Science Foundation of China(82471564)YT is supported by National Natural Science Foundation of China(32322035,32171078).
文摘Background Pain sensitivity is critical for preventing non-suicidal self-injury(NSSI)behaviours;however,individuals engaging in such behaviours often exhibit decreased pain sensitivity,which may undermine this natural safeguard.The dorsolateral prefrontal cortex(DLPFC)is a key region involved in pain regulation,and recent approaches using transcranial direct current stimulation(tDCS)to target the DLPFC have shown potential for modulating pain processing and restoring normal pain perception for individuals engaging in NSSI behaviours.Aims This study aimed to explore the immediate and short-term effects of a single session of tDCS on pain sensitivity in individuals with NSSI,as well as its secondary effects on mood and NSSI-related factors.Methods In this randomised,double-blind,parallel,sham-controlled clinical trial,participants with a history of NSSI were randomly assigned to receive either active or sham tDCS.The intervention consisted of a single 20 min tDCS session targeting the left DLPFC.The primary outcome was pain sensitivity,measured by the pressure pain threshold(PPT)and heat pain score(HPS).Secondary and additional outcomes included NSSI urges,NSSI resistance,self-efficacy in resisting NSSI,mood-related variables and exploratory cognitive-affective processes such as rumination,self-criticism and self-perceived pain sensitivity,assessed at baseline,immediately post-intervention,and at 24 hours,1 week and 2 weeks follow-ups.Results For the primary outcomes,no significant differences between groups were observed for pain sensitivity(PPT,padj=0.812;HPS,padj=0.608).However,an exploratory sensitivity analysis treating each trial as an individual observation revealed a significant effect on HPS(padj=0.036).For the secondary and additional outcomes,although there were initial improvements in joyful feelings and reductions in negative affect at 2 weeks post-intervention,these effects did not remain significant after multiple comparison corrections.Notably,reductions in rumination were statistically significant at both 1-week and 2-week follow-ups(1 week,p_(adj)=0.040;2 weeks,p_(adj)=0.042).There were no significant effects on NSSI urges,NSSI resistance,self-efficacy in resisting NSSI or self-criticism.Conclusions A single session of tDCS over the left DLPFC did not produce significant changes in pain sensitivity in individuals with NSSI.A sensitivity analysis indicated an effect on heat pain sensitivity,possibly reflecting changes in brain activity,warranting confirmation through neuroimaging.These findings suggest that tDCS warrants further investigation for its potential to influence pain-related cognitive-affective processes in individuals with NSSI.
基金supported by the National Natural Science Foundation of China (No.30770691),Beijing Municipal Government for Advancement of Sciences,and Capital Medical University for Innovation Awards
文摘Pain perception and its genesis in the human brain have been reviewed recently. In the current article, the reports on pain modulation in the human brain were reviewed from higher cortical regulation, i.e. top-down effect, particularly studied in psychological determinants. Pain modulation can be examined by gene therapy, physical modulation, pharmacological modulation, psychological modulation, and pathophysiological modulation. In psychological modulation, this article exam- ined （a） willed determination, （b） distraction, （c） placebo, （d） hypnosis, （e） meditation, （f） qi-gong, （g） belief, and （h） emotions, respectively, in the brain function for pain modulation. In each, the operational definition, cortical processing, neuroimaging, and pain modulation were systematically deliberated. However, not all studies had featured the brain modulation processing but rather demonstrated potential effects on human pain. In our own studies on the emotional modulation on human pain, we observed that emotions could be induced from music melodies or pictures perception for reduction of tonic human pain, mainly in potentiation of the posterior alpha EEG fields, likely resulted from underneath activities of precuneous in regulation of consciousness, including pain perception. To sum, higher brain functions become the leading edge research in all sciences. How to solve the information bit of thinking and feeling in the brain can be the greatest challenge of human intelligence. Application of higher cortical modulation of human pain and suffering can lead to the progress of social humanity and civilization.
文摘Spinal cord injury （SCI） currently ranks second after mental retarda- tion among neurological disorders in terms of cost to society. Pain is a debilitating consequence of SCI related to the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissues （Yezierski, 2005; D＇Angelo et al., 2013）.
基金Supported by The Veterans Administration Research Career Scientist Award(to TachéY)National Institute of Health grants No.P50 DK-64539(to TachéY)No.K01-DK088937(to Larauche M)
文摘Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of “microgenderome” related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.
基金supported by the National Natural Science Foundation of China (81161120497, 30925015, 30830044, 30900582, and 81221002)the National Basic Research Development Program (973 Program) of China (2014CB542204)
文摘Protein kinase D （PKD） is an evolutionarily-conserved family of protein kinases. It has structural, regulatory, and enzymatic properties quite different from the PKC family. Many stimuli induce PKD signaling, including G-protein-coupled receptor agonists and growth factors. PKD1 is the most studied member of the family. It functions during cell proliferation, differentiation, secretion, cardiac hypertrophy, immune regulation, angiogenesis, and cancer. Previously, we found that PKD1 is also critically involved in pain modulation. Since then, a series of studies performed in our lab and by other groups have shown that PKDs also participate in other processes in the nervous system including neuronal polarity establishment, neuroprotection, and learning. Here, we discuss the connections between PKD structure, enzyme function, and localization, and summarize the recent findings on the roles of PKD-mediated signaling in the nervous system.
基金supported by the grant from Georgian National Science Foundation,No.GNSF/ST07/6-234
文摘Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs （NSAIDs）, or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic （intraperitoneal） administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.
基金funding by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under DFG DE 1546/12-1(M.D.),559839626(M.D.),and 538291523(S.A.M.S.)funding from Ghent University BOF program grant number BOF23/PDO/073funding enabled and organized by Projekt DEAL.
文摘A remarkable study by Guo et al.,published in Cell,suggests a compelling new direction for improving pain management:biased allosteric modulation of the neurotensin receptor 1(NTSR1),using the drug-like molecule SBI-810,promotesβ-arrestin2(βarr2)recruitment while avoiding canonical G protein signaling–thereby providing robust analgesia across a plethora of rodent models of both acute and chronic pain without impairing motor function,cognition,or causing opioid-like dependency.1,2 SBI-810 is introduced as a highly promising molecule underscoring the therapeutic potential of biased and allosteric G protein-coupled receptor(GPCR)ligands to address an urgent unmet medical need.
