CD38: A Novel Modulator of Morphine Antinociception in the Spinal Cord

Abstract

Opioid analgesics remain essential for managing moderate to severe pain, but the development of tolerance and hyperalgesia limits their clinical utility. CD38 is a multifunctional enzyme that generates calcium-mobilizing second messengers and plays a role in the supraspinal actions of opioids, yet its role in pain processing and spinal opioid effects remains undetermined. In this study, we investigated the function of CD38 in basal processing of acute heat and pressure noxious stimuli and spinal morphine antinociception using wild-type (WT) and CD38 knockout (CD38KO) mice of both sexes. CD38 enzymatic activity was highest in the spinal cord and predominantly localized to astrocytes. While CD38 deletion had no effect on baseline thermal or mechanical acute nociception, spinal morphine-induced antinociception was significantly reduced in CD38KO mice across both noxious modalities, with diminished magnitude and duration of response. Morphine-induced thermal hyperalgesia was attenuated in CD38KO females but not in males, indicating a possible sex-dependent role for CD38 in opioid-induced hyperalgesia. In contrast, spinal morphine tolerance developed similarly in both genotypes, suggesting these adaptations occur independently of CD38. Morphine administration did not alter spinal CD38 activity, and μ-opioid receptor expression was comparable between WT and CD38KO mice, indicating that CD38 modulates spinal opioid antinociception downstream or parallel to MOR signaling. These findings suggest that astrocytic CD38 plays a critical role in mediating opioid-induced antinociception without contributing to opioid-induced tolerance, highlighting its potential as a novel target for enhancing opioid efficacy.