Intrathecal administration of bone marrow stromal cells and TGF-β1 alleviate chemotherapy-induced neuropathic pain in male mice

Chemotherapy-induced peripheral neuropathy (CIPN) is the de facto clinical side effect that limits the administration of anti-cancer treatments. Recently, we reported that intrathecally injected bone marrow stromal cells (BMSCs) reduced nerve trauma-induced neuropathic pain in male mice via TGF-{beta}1 signaling. In this study, we examined sex-dependent pain relief mediated by intrathecally delivered BMSCs and TGF-{beta}1 in paclitaxel (PTX)-induced CIPN. BMSCs were prepared from primary cultures of male or female mice separately. A single intrathecal injection of BMSCs, prepared from male donors, completely prevented the development of PTX-evoked mechanical allodynia in male mice. However, female mice showed no analgesic response to either male or female BMSCs. Additionally, male mice did not demonstrate an analgesic response to BMSCs from female donors. Intrathecal injection of TGF-{beta}1 neutralizing antibody reversed the analgesic action of BMSCs. Interestingly, spinal administration of TGF-{beta}1 reduced mechanical allodynia in male mice but not in female mice. Ex vivo patch-clamp recordings in spinal cord slices revealed that TGF-{beta}1 inhibited PTX-induced synaptic plasticity, i.e. increase in spontaneous excitatory synaptic currents (sEPsCs), in spinal cord neurons from male mice only. Intrathecal TGF-{beta}1 increased the paw withdrawal threshold in von Frey testing in naive mice of males but not females, and the antinociceptive effect of TGF-{beta}1 in males was blocked by orchiectomy-induced androgen deficiency. Together, these findings reveal sex dimorphism in BMSC control of mechanical pain through spinal TGF-{beta}1 signaling.