Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice

Inyang, Kufreobong E.; McDougal, Timothy A.; Ramirez, Eric D.; Williams, Marisa; Laumet, Geoffroy; Kavelaars, Annemieke; Heijnen, Cobi J.; Burton, Michael D.; Dussor, Gregory; Price, Theodore J.

doi:10.1016/j.ynpai.2019.100037

Cited by 37 publications

(26 citation statements)

References 45 publications

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“…In CIPN, for the protection of mitochondria, the inhibition of nitro-oxidative stress with novel potential drugs might also include the use of the mitochondrial protectant pifithrin-µ, which acts by inhibiting mitochondrial p53 accumulation [122,123], histone deacetylase 6 inhibitors [124], metformin [44,74,125], peroxynitrite decomposition catalysts [126], and antioxidants and anti-inflammatory cytokines, such as interleukin (IL) 10 [125,127] (Fig. 2).…”

Section: Future Outlook: Data From Preclinical Studiesmentioning

confidence: 99%

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

Sałat

2020

Pharmacol. Rep

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Background Chemotherapy-induced peripheral neuropathy (CIPN) is regarded as one of the most common dose-limiting adverse effects of several chemotherapeutic agents, such as platinum derivatives (oxaliplatin and cisplatin), taxanes, vinca alkaloids and bortezomib. CIPN affects more than 60% of patients receiving anticancer therapy and although it is a nonfatal condition, it significantly worsens patients' quality of life. The number of analgesic drugs used to relieve pain symptoms in CIPN is very limited and their efficacy in CIPN is significantly lower than that observed in other neuropathic pain types. Importantly, there are currently no recommended options for effective prevention of CIPN, and strong evidence for the utility and clinical efficacy of some previously tested preventive therapies is still limited. Methods The present article is the second one in the two-part series of review articles focused on CIPN. It summarizes the most recent advances in the field of studies on CIPN caused by oxaliplatin, the third-generation platinum-based antitumor drug used to treat colorectal cancer. Pharmacological properties of oxaliplatin, genetic, molecular and clinical features of oxaliplatin-induced neuropathy are discussed. Results Available therapies, as well as results from clinical trials assessing drug candidates for the prevention of oxaliplatininduced neuropathy are summarized. Conclusion Emerging novel chemical structures-potential future preventative pharmacotherapies for CIPN caused by oxaliplatin are reported.

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Section: Future Outlook: Data From Preclinical Studiesmentioning

confidence: 99%

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

Sałat

2020

Pharmacol. Rep

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“…Although metformin is able to activate AMPK at the same extent in neurons and microglia of male and female rats, this drug does not affect nerve injury-induced neuropathic pain in female rats. Authors suggest that this divergence could be due to the OCT2 expression between males and females (Inyang et al, 2019).…”

Section: Effects Of Metformin On Pain Neuropathic Painmentioning

confidence: 99%

“…These data add to the evidence that metformin induces its antiallodynic effects by reducing the aberrant translation induced by nerve injury. Of note, the effect of metformin in neuropathic pain is sexually dimorphic ( Inyang et al., 2019 ). Although metformin is able to activate AMPK at the same extent in neurons and microglia of male and female rats, this drug does not affect nerve injury-induced neuropathic pain in female rats.…”

Section: Effects Of Metformin On Painmentioning

confidence: 99%

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

et al. 2020

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Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/ calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

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“…A previous study in rats demonstrated that hyperalgesic priming to carrageenan does not occur in females (Joseph et al, 2003). Subsequent studies in mice and rats have shown additional sexual dimorphisms (Megat et al, 2018; Paige et al, 2018; Inyang et al, 2019), across the lifespan (Moriarty et al, 2019), but none of them have observed a similar absence of priming in female rodents. In fact, our work shows, at least with IL-6 as the priming stimulus, that the magnitude and duration of the response to PGE 2 given peripherally or intrathecally is longer in female mice than male mice.…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Paige¹,

Barba-Escobedo

Mecklenburg

et al. 2020

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Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

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Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice

Abstract: HighlightsPaclitaxel induces hyperalgesic priming in male and female mice.AMPK activators attenuate the development of hyperalgesic priming induced by paclitaxel.Narciclasine prevents and reverses paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming.

Cited by 37 publications

References 45 publications

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

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