James, J. G. | Search bioRxiv

bioRxiv2024

Mimicking opioid analgesia in cortical pain circuits

The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, yet how opioid analgesics modulate this cortical circuit remains unclear. Uncovering how opioids alter nociceptive neural dynamics to produce pain relief is essential for developing safer and more targeted treatments for chronic pain. Here we show that a population of cingulate neurons encodes spontaneous pain-related behaviors and is selectively modulated by morphine. Using deep-learning behavioral analyses combined with longitudinal neural recordings in mice, we identified a persistent shift in cortical activity patterns following nerve injury that reflects the emergence of an unpleasant, affective chronic pain state. Morphine reversed these neuropathic neural dynamics and reduced affective-motivational behaviors without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic mu-opioid receptor promoter to drive chemogenetic inhibition. This opioid-mimetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management targeting a key nociceptive cortical opioid circuit with safe, on-demand analgesia. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=40 SRC="FIGDIR/small/591113v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d294c0org.highwire.dtl.DTLVardef@123d4f4org.highwire.dtl.DTLVardef@1720deborg.highwire.dtl.DTLVardef@efc632_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Microenvironmental Ammonia Enhances T cell Exhaustion in Colorectal Cancer

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and unbiased multi-omic analyses in this model reveals a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion and decrease proliferation. CRC patients have increased serum ammonia, and our ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. Our findings indicate that ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies. Statement of SignificanceWe demonstrate that ammonia accumulates in the microenvironment of colorectal cancer. Ammonia alters T-cells redox singling leading to a decrease in T cell proliferation and an increase in T cell exhaustion. Enhancing ammonia clearance reduces tumor size, increases survival, and increases the efficacy to immunotherapies.

cancer biology↗