Anti-nociceptive actions of CART II in chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) manifests in nearly 70% of patients treated with antineoplastic drugs and persists after treatment discontinuation, thereby impacting patient quality of life. The antidepressant duloxetine (selective inhibitor of serotonin and norepinephrine uptake) offers limited pain relief, while long-term use of opioids for chronic pain carries safety risks. Thus, novel non-opioid analgesics are needed for pain management in cancer patients. Our findings show that supraspinal (in the brain) delivery of cocaine and amphetamine-regulated transcript peptide II (CART II) reverses pain-like behaviors (tactile) in male and female mice with CIPN. Multiple behavioral outputs would provide clinical face validity and bolster translatability of a given target, thus a comprehensive dose-evaluation of CART II anti-hyperalgesic effects during chronic pain states of CART II in both sexes at multiple endpoints of chronic pain in both sexes is warranted. Previous studies have uncovered broader pharmacological actions of CART II and systemic administration of a neuropeptide likely will impose a challenge, so it is critical to determine the neurochemical signaling mechanisms of CART II in CIPN. While the lack of a known receptor for CART II has prevented such mechanistic studies, we discovered that Lysophosphatidic Acid Receptor 2 (LPAR2) is a high affinity receptor for CART II in the brain. We used cellbased assays and in vivo pharmacology tools to show that supraspinal LPAR2 is necessary CART II-induced acute analgesia. However, the role of LPAR2 in chronic pain states has not been evaluated. Our findings also demonstrate that therapeutic doses of supraspinal CART II increase glutamate release in ventrolateral periaqueductal gray (vlPAG) and nucleus accumbens (NAcc) in naïve mice, and previous work shows excitatory inputs into these brain sites can relieve neuropathic pain states. However, neurotransmission during CIPN in the vlPAG and NAcc has not been fully established. The central hypothesis in this proposal is that CART II produces its anti-hyperalgesic effects via activation of LPAR2 and increased glutamate release. Thus, we propose to fully examine anti-hyperalgesic actions of this signaling pathway in vlPAG and NAcc in males and females via two independent yet interconnected aims. Aim 1 will comprehensively evaluate dose-dependent anti-hyperalgesic effects of supraspinal CART II in 4 different behavioral output measures (tactile, cold, anxiety, depression) to interrogate any sex differences in therapeutic potential for CIPN. Incorporation of a positive allosteric modulator and knockout mice will reveal if LPAR2 is necessary and sufficient for the anti-hyperalgesic actions of CART II. Aim 2 will examine CART II-mediated neurotransmission as a mechanism of action for its anti-hyperalgesic effects in CIPN. Collectively, the expected results will address significant gaps in understanding of the supraspinal mechanisms underlying neuropathic pain states and interrogate the CART II/LPAR2 axis as a novel therapeutic strategy in reversing already established CIPN.