{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Thompson JM"],"funding":["NIDA NIH HHS","NINDS NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2025.10.06.680596"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632544"],"repository":["biostudies-literature"],"pubmed_title":["Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain."],"pmcid":["PMC12632544"],"funding_grant_id":["L70 NS134089","R01 DA058755","R01 DA049924","T32 GM108539","RM1 NS135283","T32 DA007261","R01 DA056829","R01 NS130046"],"pubmed_authors":["Chang YH","Kalyanaraman V","Liu M","Xu C","Graham RD","Creed MC","Wang H","Goff JP","Hage T","Copits BA","Barrett M","George R","Kravitz A","Thompson JM","Legaria A"],"additional_accession":[]},"is_claimable":false,"name":"Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain.","description":"Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Oct","modification":"2026-06-13T03:13:12.153Z","creation":"2026-06-13T03:08:44.33Z"},"accession":"S-EPMC12632544","cross_references":{"pubmed":["41279070"],"doi":["10.1101/2025.10.06.680596"]}}