Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of cancer treatment that significantly impacts patients' quality of life. This study investigated the effects of targeting metabolic pathways on bortezomib-induced neuropathic pain and tumor growth using a Lewis lung carcinoma (LLC) mouse model, while exploring potential sex differences. Methods: Male and female C57BL/6J mice were implanted with LLC cells and treated with bortezomib alone or in combination with metformin, dichloroacetate (DCA), or oxamate. Tactile allodynia was assessed using von Frey filaments. Tumor volume and weight were measured to evaluate tumor growth. Results: Metformin, DCA, and oxamate effectively attenuated bortezomib-induced neuropathic pain without compromising the anticancer efficacy of bortezomib in both male and female mice. The LLC model exhibited a paraneoplastic neuropathy-like phenotype. Significant sex differences were observed, with male mice exhibiting larger tumors compared to females. Oxamate was more effective in alleviating allodynia in males, while metformin and DCA showed greater efficacy in reducing tumor growth in females. Discussion: Targeting metabolic pathways can alleviate CIPN without interfering with bortezomib's anticancer effects. The LLC model may serve as a tool for studying paraneoplastic neuropathy. Sex differences in tumor growth and response to metabolic interventions highlight the importance of considering sex as a biological variable in preclinical and clinical studies investigating cancer biology, CIPN, and potential therapeutic interventions.

Valproate attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress through inhibiting spinal IL-6 and STAT1 phosphorylation.

Temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) may present as comorbid conditions, but treatment options are ineffective. The purpose of this study was to investigate whether valproate (VPA) attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress, which represents a model of pain associated with TMD and FMS comorbidity, and to explore the potential mechanisms. The results showed that VPA inhibited somatic hyperalgesia induced by orofacial inflammation combined with stress, and down-regulated the interleukin-6 (IL-6) expression in the L4-L5 spinal dorsal horn of female rats. The anti-nociceptive effect of VPA was blocked by single or 5 consecutive day intrathecal administration of recombinant rat IL-6. Orofacial inflammation combined with stress up-regulated the ratio of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) to STAT1 (p-STAT1/STAT1) in the spinal cord. VPA did not affect the STAT1 expression, while it down-regulated the ratio of p-STAT1/STAT1. The expression of STAT3 and the ratio of p-STAT3/STAT3 were not affected by orofacial inflammation combined with stress and VPA treatment. Intrathecal administration of exogenous IL-6 up-regulated the ratio of p-STAT1/STAT1. These data indicate that VPA attenuated somatic hyperalgesia induced by orofacial inflammation combined with stress via inhibiting spinal IL-6 in female rats, and the mechanism may involve the alteration of activation status of spinal STAT1. Thus, VPA may be a new candidate analgesic that targets IL-6 and STAT1 for the treatment of pain associated with the comorbidity of TMD and FMS.

Chronic stress induces wide-spread hyperalgesia: The involvement of spinal CCK1 receptors.

Chronic primary pain (CPP) occurs in the absence of tissue injury and includes temporomandibular disorders (TMD), fibromyalgia syndrome (FMS) and irritable bowel syndrome (IBS). CPP is commonly considered a stress-related chronic pain and often presents as wide-spread pain or comorbid pain conditions in different regions of the body. However, whether prolonged stress can directly result in the development of CPP comorbidity remains unclear. In the present study, we adapted a 21 day heterotypic stress paradigm in mice and examined whether chronic stress induced wide-spread hyperalgesia, modeling comorbid CPP in the clinic. We found that chronic stress induced anxiety- and depression-like behaviors, and resulted in long-lasting wide-spread hyperalgesia over several body regions such as the orofacial area, hindpaw, thigh, upper back and abdomen in female mice. We further found that the expression of cholecystokinin (CCK)1 receptors was significantly increased in the L4-L5 spinal dorsal horn of the female mice after 14 and 21 day heterotypic stress compared with the control animals. Intrathecal injection of the CCK1 receptor antagonist CR-1505 blocked pain hypersensitivity in the subcervical body including the upper back, thigh, hindpaw and abdomen. These findings suggest that the upregulation of spinal CCK1 receptors after chronic stress contributes to the central mechanisms underlying the development of wide-spread hyperalgesia, and may provide a potential and novel central target for clinical treatment of CPP.