Featured Publications
A nociceptive amygdala-striatal pathway modulating affective-motivational pain
Wojick et al. Science Advances. 2025 (cover)
The basolateral amygdala (BLA) assigns valence to sensory stimuli, with a dedicated nociceptive ensemble encoding the negative valence of pain. However, the effects of chronic pain on the transcriptomic signatures and projection architecture of this BLA nociceptive ensemble are not well understood. Here, we show that optogenetic inhibition of the nociceptive BLA ensemble reduces affective-motivational behaviors in chronic neuropathic pain. Single-nucleus RNA sequencing revealed peripheral injury–induced changes in genetic pathways involved in axonal and presynaptic organization in nociceptive BLA neurons. Next, we identified a previously uncharacterized nociceptive hotspot in the nucleus accumbens shell that is innervated by BLA nociceptive neurons. Axonal calcium imaging of BLA projections to the accumbens and chemogenetic inhibition of this pathway revealed pain-related transmission from the amygdala to the medial nucleus accumbens, facilitating both acute and chronic pain affective-motivational behaviors. Together, this work defines a critical nociceptive amygdala-striatal circuit underlying pain unpleasantness across pain states.
Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles
Rogers, Heller, Corder. Nature Neuroscience. 2025
The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility. However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay. We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction. In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.
An amygdalar neural ensemble that encodes the unpleasantness of pain
Pain is an unpleasant experience. How the brain’s affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of time-lapse in vivo calcium imaging and neural activity manipulation in freely behaving mice encountering noxious stimuli, we identified a distinct neural ensemble in the basolateral amygdala that encodes the negative affective valence of pain. Silencing this nociceptive ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerve injury, innocuous stimuli activated this nociceptive ensemble to drive dysfunctional perceptual changes associated with neuropathic pain, including pain aversion to light touch (allodynia). These results identify the amygdalar representations of noxious stimuli that are functionally required for the negative affective qualities of acute and chronic pain perception.
Corder et al. Nature Medicine 2017 (cover)
Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.
Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence
Corder et al. Science. 2013 (cover)
Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced μ-opioid receptor (MOR) constitutive activity (MORCA) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3′,5′-monophosphate overshoot and hyperalgesia) that required N-methyl-D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MORCA initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MORCA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.
Structure-based discovery of opioid analgesics with reduced side effects
Manglik et al. Nature. 2016 (cover)
Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.
Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits
Wang et al. Neuron. 2018 (cover)
Cellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivoremains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics.
VTA µ-Opioidergic Neurons Facilitate Low Sociability in Protracted Opioid Abstinence
Jo et al. J Neurosci. 2025 (cover)
Opioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted abstinence is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and μ-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTAMOR neurons in mediating protracted abstinence-induced negative affect is not fully understood. In our study, we elucidate the role of VTAMOR neurons in mediating negative affect and altered brain-wide neuronal activities following forced opioid exposure and abstinence in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted forced abstinence. VTAMOR neurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knock-out mice demonstrates that the disrupted social interaction observed during protracted abstinence is facilitated by this neural population, without affecting other protracted abstinence behaviors. Lastly, VTAMORs contribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTAMOR neurons as critical modulators of low sociability during protracted abstinence and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid abstinence.
Salimando et al. Nature Communications. 2023
With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.
Engineered serum markers for non-invasive monitoring of gene expression in the brain
Lee et al. Nature Biotechnology. 2024
Measurement of gene expression in the brain requires invasive analysis of brain tissue or non-invasive methods that are limited by low sensitivity. Here we introduce a method for non-invasive, multiplexed, site-specific monitoring of endogenous gene or transgene expression in the brain through engineered reporters called released markers of activity (RMAs). RMAs consist of an easily detectable reporter and a receptor-binding domain that enables transcytosis across the brain endothelium. RMAs are expressed in the brain but exit into the blood, where they can be easily measured. We show that expressing RMAs at a single mouse brain site representing approximately 1% of the brain volume provides up to a 100,000-fold signal increase over the baseline. Expression of RMAs in tens to hundreds of neurons is sufficient for their reliable detection. We demonstrate that chemogenetic activation of cells expressing Fos-responsive RMA increases serum RMA levels >6-fold compared to non-activated controls. RMAs provide a non-invasive method for repeatable, multiplexed monitoring of gene expression in the intact animal brain.
AxoDen: An Algorithm for the Automated Quantification of Axonal Density in Defined Brain Regions
Sandoval Ortega et al. eNeuro. 2025
The rodent brain contains 70,000,000+ neurons interconnected via complex axonal circuits with varying architectures. Neural pathologies are often associated with anatomical changes in these axonal projections and synaptic connections. Notably, axonal density variations of local and long-range projections increase or decrease as a function of the strengthening or weakening, respectively, of the information flow between brain regions. Traditionally, histological quantification of axonal inputs relied on assessing the fluorescence intensity in the brain region of interest. Despite yielding valuable insights, this conventional method is notably susceptible to background fluorescence, postacquisition adjustments, and inter-researcher variability. Additionally, it fails to account for nonuniform innervation across brain regions, thus overlooking critical data such as innervation percentages and axonal distribution patterns. In response to these challenges, we introduce AxoDen, an open-source semiautomated platform designed to increase the speed and rigor of axon quantifications for basic neuroscience discovery. AxoDen processes user-defined brain regions of interests incorporating dynamic thresholding of grayscale-transformed images to facilitate binarized pixel measurements. Here, in mice, we show that AxoDen segregates the image content into signal and nonsignal categories, effectively eliminating background interference and enabling the exclusive measurement of fluorescence from axonal projections. AxoDen provides detailed and accurate representations of axonal density and spatial distribution. AxoDen's advanced yet user-friendly platform enhances the reliability and efficiency of axonal density analysis and facilitates access to unbiased high-quality data analysis with no technical background or coding experience required. AxoDen is ad libitum available to everyone as a valuable neuroscience tool for dissecting axonal innervation patterns in precisely defined brain regions.
PREPRINTS
Mimicking opioid analgesia in cortical pain circuits. Justin G. James, Nora M. McCall, Alex I. Hsu, Corinna S. Oswell, Gregory J. Salimando, Malaika Mahmood, Lisa M. Wooldridge, Meghan Wachira, Adrienne Jo, Raquel Adaia Sandoval Ortega, Jessica A. Wojick, Katherine Beattie, Sofia A. Farinas, Samar N. Chehimi, Amrith Rodrigues, Lindsay L. Ejoh, Blake A. Kimmey, Emily Lo, Ghalia Azouz, Jose J. Vasquez, Matthew R. Banghart, Kate Townsend Creasy, Kevin T. Beier, Charu Ramakrishnan, Richard C. Crist, Benjamin C. Reiner, Karl Deisseroth, Eric A. Yttri, Gregory Corder. bioRxiv. 2024. https://www.biorxiv.org/content/10.1101/2024.04.26.591113v1
Convergent state-control of endogneous opioid analgesia. Blake A Kimmey, Lindsay Ejoh, Lily Shangloo, Jessica A Wojick, Samar Nasser Chehimi, Nora M McCall, Corinna S Oswell, Malaika Mahmood, Lite Yang, Vijay K Samineni, Charu Ramakrishnan, Karl Deisseroth, Richard C Crist, Benjamin C Reiner, Lin Tian, Gregory Corder. bioRxiv. 2025. https://www.biorxiv.org/content/10.1101/2025.01.03.631111v1
Central amygdalar PKCδ neurons mediate fentanyl withdrawal. Lisa M. Wooldridge, Jacqueline W.K. Wu, Adrienne Y. Jo, Morgan Zinn, Angela M. Lee, Malaika Mahmood, Savanna A. Cohen, Gregory Corder. bioRxiv. 2025. https://www.biorxiv.org/content/10.1101/2025.02.21.639538v1
Modeling Withdrawal States in Opioid-Dependent Mice with Machine Learning. Savanna A. Cohen, Lisa M. Wooldridge, Justin J. James, Jacqueline W. K. Wu, Gregory Corder. bioRxiv. 2025. https://www.biorxiv.org/content/10.1101/2025.07.29.667254v1
publications
* denotes equal contributions
Engineered serum markers for non-invasive monitoring of gene expression in the brain. Sangsin Lee, Shirin Nouraein, James J Kwon, Zhimin Huang, Jessica A Wojick, Boao Xia, Gregory Corder, Jerzy O Szablowski. Nature Biotechnology. 2024. https://www.nature.com/articles/s41587-023-02087-x
Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types. Gregory J Salimando, Sébastien Tremblay, Blake A Kimmey, Jia Li, Sophie A Rogers, Jessica A Wojick, Nora M McCall, Lisa M Wooldridge, Amrith Rodrigues, Tito Borner, Kristin L Gardiner, Selwyn S Jayakar, Ilyas Singeç, Clifford J Woolf, Matthew R Hayes, Bart C De Jonghe, F Christian Bennett, Mariko L Bennett, Julie A Blendy, Michael L Platt, Kate Townsend Creasy, William R Renthal, Charu Ramakrishnan, Karl Deisseroth, Gregory Corder. Nature Communications. 2023. https://www.nature.com/articles/s41467-023-41407-2
Structural imaging studies of patients with chronic pain: an anatomical likelihood estimate meta-analysis. Alina T Henn, Bart Larsen, Lennart Frahm, Anna Xu, Azeez Adebimpe, J Cobb Scott, Sophia Linguiti, Vaishnavi Sharma, Allan I Basbaum, Gregory Corder, Robert H Dworkin, Robert R Edwards, Clifford J Woolf, Ute Habel, Simon B Eickhoff, Claudia R Eickhoff, Lisa Wagels, Theodore D Satterthwaite. Pain. 2023. https://journals.lww.com/pain/abstract/2023/01000/structural_imaging_studies_of_patients_with.5.aspx
A novel Oprm1-Cre mouse maintains endogenous expression, function and enables detailed molecular characterization of μ-opioid receptor cells. Juliet Mengaziol, Amelia D Dunn, Gregory Salimando, Lisa Wooldridge, Jordi Crues-Muncunill, Darrell Eacret, Chongguang Chen, Kathryn Bland, Lee-Yuan Liu-Chen, Michelle E Ehrlich, Gregory Corder, Julie A Blendy. PLOS One. 2022. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0270317
Xu A, Larsen B, Henn A, Baller EB, Scott JC, Sharma V, Adebimpe A, Basbaum AI, Corder G, Dworkin RH, Edwards RR, Woolf CJ, Eickhoff SB, Eickhoff CR, Satterthwaite TD. Brain Responses to Noxious Stimuli in Patients With Chronic Pain: A Systematic Review and Meta-analysis. JAMA Network Open. 2021 Jan 4;4(1):e2032236. doi: 10.1001/jamanetworkopen.2020.32236. PMID: 33399857
Jones, J, Foster, W Twomey, C Burdge, J, Ahmed,O, Wojick JA, Corder G, Plotkin, JB, Abdus-Saboor, I. A machine-vision approach for automated pain measurement at millisecond timescales. eLife. 2020 Aug 6;9:e57258. doi: 10.7554/eLife.57258
Corder, G*, Ahanonu, B*, Grewe, B, Wang, D, Schnitzer, MJ, Scherrer, G. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science. 2019 Jan. 18; 363(6424):276-281. doi: 10.1126/science.aap8586. PMID: 3065440
Nelson TS, Fu W, Donahue RR, Corder GF, Hökfelt T, Wiley RG, Taylor BK. Facilitation of neuropathic pain by the NPY Y1 receptor-expressing subpopulation of excitatory interneurons in the dorsal horn. Scientific Reports. 2019 May 10;9(1):7248. doi: 10.1038/s41598-019-43493-z.
Corder, G*, Tawfik, VL*, Wang, D*, Sypek, ES*, Low, SA, Dickinson, JR, Sotoudeh, C, Clark, JD, Barres, B, Bohlen, C Scherrer, G. Loss of μ-opioid receptor signaling in nociceptors, and not spinal microglia, abrogates morphine tolerance without disrupting analgesia. Nature Medicine. 2017 Feb; 23(2):164-173. doi: 10.1038/nm.4262.
Wang, D, Tawfik, VL, Corder, G, Low, SA, Basbaum, AI, Scherrer, G. Functional Divergence of Delta and Mu Opioid Receptors Organization in CNS Pain Circuits. Neuron. 2018 Apr 4;98(1):90-108.e5. doi: 10.1016/j.neuron.2018.03.002.
Manglik, A*, Henry, L*, Aryal, DP*, McCorvy, JD, Dengler, D, Corder, G, Bernat, V, Huang, X, Sassano, MF, Giguere, PM, Levit, A, Lober, S, Hubner, H, Duan, D, Scherrer, G, Kobilka, BK, Gmeiner, P, Roth, BL, Shoichet, BK. Structure-based discovery of biased μ-opioid receptor analgesics with reduced side effects. Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112.
Rowe R, Ellis G, Harrison J, Bachstetter A, Corder GF, Van Eldik L, Taylor BK, Marti F, Lifshitz J. Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge. Molecular Pain. 2016 May 13;12. doi: 10.1177/1744806916647055.
Taylor, BK, Fu, W, Kuphal, KE, Stiller, CO, Winter, MK, Chen, W, Corder, GF, Urban, JH, McCarson, KE, Marvizon, JC. Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons. Neuroscience. 2014 Jan 3;256:178-94. doi: 10.1016/j.neuroscience.2013.10.054.
Corder, G, Doolen, S, Winter, MW, Jutras, BL, He, Y, Hu, X, Wieskopf, JS, Mogil, JS, Storm, DR, Wang, ZJ, McCarson, KE, Taylor, BK. Constitutive µ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013 Sep 20;341(6152):1394-9. doi: 10.1126/science.1239403.
Solway, BM, Bose, S, Corder, G, Donahue, R, Taylor, BK. Tonic inhibition of chronic pain by Neuropeptide Y. PNAS, USA. 2011 Apr 26;108(17):7224-9. doi: 10.1073/pnas.1017719108.
Corder, G, Siegel, A, Intondi, AB, Zhang, X, Zadina, JE, Taylor, BK. A novel method to quantify histochemical changes throughout the mediolateral axis of the substantia gelatinosa after spared nerve injury: characterization with TRPV1 and substance P. Journal of Pain. 2010 Apr;11(4):388-98. doi: 10.1016/j.jpain.2009.09.008.
Reviews / Book Chapters
Broadening our conceptual understanding of endogenous opioids in systems neuroscience. Hugo A Tejeda, Nicolas Massaly, Gregory Corder, Catherine M Cahill. Frontiers in Systems Neuroscience. 2023. https://www.frontiersin.org/journals/systems-neuroscience/articles/10.3389/fnsys.2023.1212650/full
Ahanonu, B, Corder, G. Chapter: Recording Pain-related Brain Activity in Behaving Animals using Calcium Imaging and Miniature Microscopes. Book: Contemporary approaches to the study of pain: from molecules to neural networks. Editor: Rebecca Seal. Publisher: Springer Nature. In Press.
Kimmey BA, McCall NM, Wooldridge LM, Satterthwaite TD, Corder G. Engaging endogenous opioid circuits in pain affective processes. Journal Neuroscience Research. 2020 Dec 13. doi: 10.1002/jnr.24762
McCall, N, Wojick, J, Corder, G. Anesthesia Analgesia in the Amygdala. Nature Neuroscience, News & Views. 2020 May. Doi: 10.1038/s41593-020-0645-3
Corder, G*, Castro, D*, Bruchas, M, Scherrer, G. Exogenous and endogenous opioids in pain. Annual Review of Neuroscience. 2018 Jul 8;41:453-473. doi: 10.1146/annurev-neuro-080317-061522.
Taylor, BK and Corder, G. Endogenous analgesia, dependence, and latent pain sensitization. Current Topics in Behavioral Neuroscience. 2014 Sep 17. doi 10.1007/7854_2014_351. PMID: 25227929.
Dissertation (s)
Corder, G. Injury Establishes Constitutive μ-Opioid Receptor Signaling Leading to Lasting Endogenous Analgesia and Dependence. University of Kentucky. 2013. http://uknowledge.uky.edu/physiology_etds/10/