This study by Stockstill et al. demonstrates that bortezomib-induced neuropathic pain is driven by S1P receptor 1 (S1PR1) activation in spinal cord astrocytes. Disrupting spinal astrocyte S1PR1 signaling attenuates neuropathic pain by reducing neuroinflammation and presynaptic glutamate release.

Chemotherapy-induced neuropathic pain (CINP) in both sexes compromises many current chemotherapeutics and lacks a FDA-approved therapy. We recently identified the sphingosine-1phosphate receptor subtype 1 (S1PR1) and A 3 adenosine receptor subtype (A 3 AR) as novel targets for therapeutic intervention. Our work in male rodents using paclitaxel, oxaliplatin and bortezomib showed robust inhibition of CINP with either S1PR1 antagonists or A 3 AR agonists. The S1PR1 functional antagonist FTY720 (Gilenya®) is FDA approved for treating multiple sclerosis and selective A 3 AR agonists are in advanced clinical trials for cancer and inflammatory disorders, underscoring the need for their expedited trials in CINP patients as chemotherapy adjuncts. Our findings reveal that S1PR1 antagonists and A 3 AR agonists mitigate paclitaxel and oxaliplatin CINP in female and male rodents, but failed to block or reverse bortezomib-induced neuropathic pain (BINP) in females. Although numerous mechanisms likely underlie these differences, we focused on receptor levels. We found that BINP in male rats, but not female rats, was associated with increased expression of A 3 AR in spinal cord dorsal horn, while S1PR1 levels were similar in both sexes. Thus, alternative mechanisms beyond receptor expression may account for sex differences in response to S1PR1 antagonists. Morphine and duloxetine, both clinical analgesics, reversed BINP in female mice, demonstrating that the lack of response is specific to S1PR1 and A 3 AR agents. Our findings suggest that A 3 AR-and S1PR1-based therapies are not viable approaches in preventing and treating BINP in females and should inform future clinical trials of these drugs as adjuncts to chemotherapy.

Stress (195) Altered tropomysin receptor kinase B (TrkB) protein expression in the hypothalamus links to prolonged stress-induced enduring mechanical allodynia in na€ ıve and thermal injured rats

e18705 Background: Patients diagnosed with persistent, recurrent, or metastatic cervical cancer (CC) may face uncertainty about treatment options, impact of treatment on health & quality of life (QoL), & available resources. This study provides insight into patient concerns & information seeking (IS) behaviors. Methods: In January 2021, semi-structured telephone interviews were conducted in the US with CC patients (diagnosed within 2 years) recruited through panels, social media & advocacy groups. The interview focused on rational & emotional drivers and barriers for IS. Transcripts were coded using NVivo qualitative analysis software to identify key themes. Results: 14 women of varied education status were interviewed (mean age 51 years (range: 37-70); 8 White, 4 Black, & 2 Latina). Patients emphasized trust in their oncologist to provide sufficient information. IS was driven by the desires to confirm their oncologist’s recommendation & find reassurance through the experience of other patients, and encouragement from family. Barriers to IS included: 1) hesitancy to undermine their oncologist’s recommendations, 2) pessimism about ability to find individualized answers about prognosis or QoL, 3) feeling overwhelmed & fearing mis-information, 4) personal urgency to decide on a treatment plan, 5) already having sufficient information, 6) potential exposure to “negative energy” from online patient communities, & 7) COVID-19 hindering opportunity for personal connections. Conclusions: While patients’ oncologist, family, & common patient experience provide comfort, reluctance towards IS exists. As trusted gatekeepers, oncologists should recognize patients’ desire for accessible, reliable, & personalized information. Better understanding this perspective and gaps in the availability of validated & relevant resources can enable clinicians/policy makers to develop strategies & tools for better communication. In turn, this will help CC patients feel more empowered & informed throughout their cancer care journey.[Table: see text]

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