Abstract
Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. In the mechanical allodynia testing, U50,488 was more potent in males and SalA was more potent in females. There were no sex differences in the acute cold allodynia testing. In the chronic administration model, treatment with U50,488 (10 mg/kg) reduced the mechanical and cold allodynia responses to healthy levels over 23 days of treatment. Overall, we have shown that KOR agonists are effective in a model of chemotherapy-induced neuropathic pain, indicating that KOR agonists could be further developed to treat this debilitating condition.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of treating cancer (Sisignano et al, 2014; Addington and Freimer, 2016) with 68% of chemotherapy patients reporting CIPN within the first month of treatment (Seretny et al, 2014)
This study aimed to understand the effects of Kappa opioid receptor (KOR) agonists (Figure 1) for the treatment of paclitaxel-induced neuropathic pain in male and female mice
We have investigated the effect of KOR agonists for the treatment of paclitaxel-induced neuropathic pain due to the reduced abuse potential of KOR agonists, which is an important requirement for these treatments due to the longterm nature of chemotherapy regimens
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of treating cancer (Sisignano et al, 2014; Addington and Freimer, 2016) with 68% of chemotherapy patients reporting CIPN within the first month of treatment (Seretny et al, 2014). Often CIPN is identified as the reason for limiting either the dose or length of chemotherapy treatment and in severe CIPN cases, chemotherapy may be terminated (Holmes et al, 1991; Rowinsky et al, 1993); CIPN may persist for months following cessation of chemotherapy (van den Bent et al, 1997). Chemotherapy drugs that induce CIPN include vinca alkaloids, platinum derivatives and taxanes (Jaggi et al, 2011; Sisignano et al, 2014; Ewertz et al, 2015). Paclitaxel is a Salvinorin-A Analogues Attenuate Neuropathic Pain taxane chemotherapeutic widely used to treat solid tumors such as ovarian, breast, cervical, prostate, non-small cell lung, gastric, head and neck, Kaposi’s sarcoma, and pancreatic cancers (Khanna et al, 2015)
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