Sexually dimorphic therapeutic response in bortezomib-induced neuropathic pain reveals altered pain physiology in female rodents

Abstract

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.

Targeting the Sphingosine-1-Phosphate Axis for Developing Non-narcotic Pain Therapeutics

“…Moreover, mice with specific deletion of S1PR1 on astrocytes do not develop CINP, underscoring the importance of an astrocyte-based S1PR1 signaling pathway in these conditions [99]. Importantly, sex differences in drug responses to bortezomib-induced neuropathic pain (BINP) have been reported [111]. In particular, S1PR1 antagonists, which alleviate paclitaxel and oxaliplatin CINP in both sexes, failed to prevent and reverse BINP in female rodents [111].…”

“…Importantly, sex differences in drug responses to bortezomib-induced neuropathic pain (BINP) have been reported [111]. In particular, S1PR1 antagonists, which alleviate paclitaxel and oxaliplatin CINP in both sexes, failed to prevent and reverse BINP in female rodents [111]. These data are particularly relevant and have to be considered in the clinical translation of these compounds, since S1PR1-based therapies could be ineffective in the treatment of CINP in women who receive bortezomib chemotherapy.…”

“…[36] CLCN3 and CLCN5 mediate excitatory Clcurrents activated by S1P/S1PR3 in mouse sensory neurons 2018 [71] S1P-to-S1PR3 signaling mediates pain behaviors in mice through the activation of TRPV1 in sensory neurons 2018 [61] Sexual dysmorphic responses are observed with bortezomib. Unlike paclitaxel and oxaliplatin, S1PR1-based therapies do not block bortezomib-induced neuropathic pain in female rats and mice 2019 [111] Ceramide-induced pain behaviors in mice involve NLRP2 inflammasome activation in the DRG 2019 [50] Activation of S1PR1 in spinal astrocytes, following intrathecal injection of SEW2871, leads to NLRP3 inflammasome activation, IL-1β production, and pain behaviors in mice and rats 2019 [81] Functional and competitive S1PR1 antagonists block traumatic nerve injury-induced neuropathic pain in mice and rats. S1PR1 expressed on astrocytes is identified as a target for therapeutic intervention with S1PR1 antagonists 2019 [84] S1PR2 activation in spinal cord attenuates neuropathic pain and neuroinflammation in a model of traumatic nerve injury in rats 2019 [91] Clinical trials for proof of concept in patients with breast cancer have begun with fingolimod to explore efficacy in preventing and/or treating chemo-induced neuropathic pain (NCTID: NCT03941743; NCT03943498) 2019 i FTY720 ameliorates spinal cord injury induced-neuropathic pain in rats by dampening neuroinflammation and inhibiting glial scar formation 2020 [97] Role for S1PR1 in opioid-mediated adverse events is identified.…”

Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice

“…It has been reported that sphingosine-1-phosphate receptor subtype 1 (S1PR1) antagonists and A 3 adenosine receptor subtype (A 3 AR) agonists suppressed the oxaliplatin- and paclitaxel-induced neuropathy in male and female rats, but S1PR1 antagonists and A 3 AR agonists only inhibited the bortezomib-induced neuropathy in male rats. [ 64 ]. It has also indicated that resolvin D5 inhibited the paclitaxel-induced mechanical allodynia in male mice, but did not affect female mice [ 65 ].…”

The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain

“…Inhibition of sphingosine-kinase blocks the neuroprotective effect of NGF, suggesting that S1P is involved in NGF-mediated survival in neuron cultures, and the excitatory effect of NGF introducing nociceptor sensitization and hyperalgesia also dependents on S1P production [146,227]. To some extent, the precise contribution of S1P1 and S1P2 as potential analgesic drug targets for paclitaxel, oxaliplatin, and bortezomib induced neuropathic pain are conversely discussed and even sex differences in responses to S1P receptor antagonists are reported [228]. Altogether, drugs targeting the ceramide to S1P pathway, specifically S1P2 agonists, are more and more emerging as an adjuvant therapeutic strategy for enhancing chemotherapy effectiveness and reduction of painful neuropathies and thus may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.…”