The α7 nicotinic receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy in mice without tolerance or altering nicotine reward and withdrawal

Toma, Wisam; Kyte, S. Lauren; Bağdaş, Deniz; Jackson, Asti; Meade, Julie A.; Rahman, Faria; Chen, Zhijian; Fabbro, Egidio Del; Cantwell, Lucas; Kulkarni, Abhijit; Thakur, Ganesh A.; Papke, Roger L.; Bigbee, John W.; Gewirtz, David A.; Damaj, M. Imad

doi:10.1016/j.expneurol.2019.113010

Cited by 27 publications

(25 citation statements)

References 58 publications

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“…To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. Cholinergic M receptors Benztropine M receptor antagonism-neuronal density loss prevention [149] Cholinergic N receptors R-47 N receptor stimulation-Intraepidermal nerve fiber loss prevention [150,151] NOP receptors Cebranopadol NOP agonism-cold allodynia/hyperalgesia prevention [153] Adrenergic β receptors Carvedilol β receptor antagonism and ROS inhibition-intraepidermal nerve fiber loss prevention [4] TRPA1 channels HC-030031, and analogs TRPA1 antagonism-tactile allodynia and cold allodynia/hyperalgesia reduction [154] Na v channels Ambroxol Na v channel inhibition-decreased neuronal cell excitability [156]…”

Section: Resultsmentioning

confidence: 99%

“…No tolerance developed following repeated administration of R-47, and R-47 lacked intrinsic rewarding effects. Additionally, R-47 did not influence the rewarding effects of nicotine in the conditioned place preference test in mice, and it did not enhance mecamylamineprecipitated withdrawal [151].…”

Section: Future Outlook: Data From Preclinical Studiesmentioning

confidence: 86%

“…A primary concern is that nicotine may also stimulate tumor growth, and smoking history has been classified as a risk factor for CIPN. The research is focused on nicotinic receptor agonists as novel strategies for the prevention and treatment of CIPN [150,151].…”

Section: Future Outlook: Data From Preclinical Studiesmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Future Outlook: Data From Preclinical Studiesmentioning

confidence: 86%

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

Sałat

2020

Pharmacol. Rep

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“…Separate from the α9α10 nAChR subtype, the closely-related homomeric α7 nAChR and the α74β2 nAChR subtypes have been implicated in the modulation of pain. Selective activation of α7 nAChRs with (R)-(-)-3-methoxy-1-oxa-2,7-diaza-7,10ethanospiro[4.5]dec-2-ene sesquifumarate ((R)-ICH3) or PNU-282987, positive allosteric modulation with GAT107 or PNU-120596, and silent agonism with (R)-N-(4-Methoxyphenyl)-2-((pyridin-3-yloxy)methyl)pi-perazine-1-carboxamide Dihydrochloride (R-47) have shown efficacy in models of inflammatory and neuropathic pain [75][76][77][78]. Separately, the α4β2 nAChR agonist (R)-5-(2azetidinylmethoxy)-2-chloropyridine (ABT-594), an analog inspired by the alkaloid epibatidine isolated from poison arrow frog, Epipedobates tricolor, has been shown to result in robust anti-pain effects [79,80].…”

Section: Chemotherapy-induced Neuropathic Pain and Block Of α9α10 Nachrsmentioning

confidence: 99%

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

et al. 2019

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Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.Patients have exhibited several types of neuropathies, including numbness, chronic pain, and allodynia (painful hypersensitivity) to mechanical or thermal stimuli [5]. Amongst patients, however, the type, duration, and severity of neuropathy can vary [6]. While the prevalence and manifestations of paclitaxel-induced neuropathy have been well documented, the underlying mechanisms are still being characterized. Several adjuvant treatments have been used in an attempt to combat the effects of chemotherapy-induced peripheral neuropathy (CIPN). However, there are currently no FDA-approved medications for the prevention or treatment of CIPN.Cone snails have historically displayed a repertoire of therapeutic molecules. The venomous marine gastropods of the genus Conus are a diverse collection of snails that have developed complex hunting and envenomation strategies. The venoms of these snails contain hundreds of unique peptides, and the contents of these venoms can also change in response to defensive or predatory stimuli [7]. Cone snails have refined a suite of bioactive peptides that can exquisitely and potently discriminate among receptors involved in neurotransmission. These targets include G-protein-coupled receptors and voltage-and ligand-gated ion channels [8]. The chemical arsenal of each snail also contains bioactive compounds that have been characterized as prey-endogenous mimetics, such as the insulin-like peptide used by Conus geographus, which more closely resembles fish insulin than its own [9]. The discovery of this molecular mimicry strategy spurred the characterization of several other hormone/neuropeptide-like peptides in the venom reperto...

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“…Burrowing, wheel running, CPP, adhesive recognition test (Park et al, 2013;Flatters et al, 2017;Laumet et al, 2019;Toma et al, 2019;Bruna et al, Open field, CPP, hunching, vocalization (Roughan et al, 2004b;Roughan et al, 2014) Frontiers in Pharmacology | www.frontiersin.org…”

Section: Spontaneousmentioning

confidence: 99%

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

2020

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The incidence of pain in cancer patients during diagnosis and treatment is exceedingly high. Although advances in cancer detection and therapy have improved patient prognosis, cancer and its treatment-associated pain have gained clinical prominence. The biological mechanisms involved in cancer-related pain are multifactorial; different processes for pain may be responsible depending on the type and anatomic location of cancer. Animal models of cancer-related pain have provided mechanistic insights into the development and process of pain under a dynamic molecular environment. However, while cancer-evoked nociceptive responses in animals reflect some of the patients’ symptoms, the current models have failed to address the complexity of interactions within the natural disease state. Although there has been a recent convergence of the investigation of carcinogenesis and pain neurobiology, identification of new targets for novel therapies to treat cancer-related pain requires standardization of methodologies within the cancer pain field as well as across disciplines. Limited success of translation from preclinical studies to the clinic may be due to our poor understanding of the crosstalk between cancer cells and their microenvironment (e.g., sensory neurons, infiltrating immune cells, stromal cells etc.). This relatively new line of inquiry also highlights the broader limitations in translatability and interpretation of basic cancer pain research. The goal of this review is to summarize recent findings in cancer pain based on preclinical animal models, discuss the translational benefit of these discoveries, and propose considerations for future translational models of cancer pain.

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The α7 nicotinic receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy in mice without tolerance or altering nicotine reward and withdrawal

Cited by 27 publications

References 58 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

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

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