The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonly used drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel and paclitaxel which interfere with the cancer cell cycle – leading to cell death and tumor degradation – and cause severe acute and chronic peripheral neuropathies We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches

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Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund’s adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.

/pdf/interleukin-6-an-emerging-regulator-of-pathological-pain-1t87av87l2.pdf

Interleukin-6: an emerging regulator of pathological pain

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with chemotherapy, but researchers rarely study its risk factors, fall risk, and prevalence in long-term breast cancer survivors. We aimed to determine CIPN prevalence, risk factors, and association with psychological distress and falls among long-term breast cancer survivors. We conducted Cross-sectional analyses among postmenopausal women with a history of stage I–III breast cancer who received taxane-based chemotherapy. Participants reported neuropathic symptoms of tingling/numbness in hands and/or feet on a 0–10 numerical rating scale. We conducted multivariate logistic regression analyses to evaluate risk factors associated with the presence of CIPN and the relationship between CIPN and anxiety, depression, insomnia, and patient-reported falls. Among 296 participants, 173 (58.4 %) reported CIPN symptoms, 91 (30.7 %) rated their symptoms as mild, and 82 (27.7 %) rated them moderate to severe. Compared with women of normal weight, being obese was associated with increased risk of CIPN (adjusted OR 1.94, 95 % CI: 1.03–3.65). Patients with CIPN reported greater insomnia severity, anxiety, and depression than those without (all p < 0.05). Severity of CIPN was associated with higher rates of falls, with 23.8, 31.9, and 41.5 % in the “no CIPN,” “mild,” and “moderate-to-severe” groups, respectively, experiencing falls (p = 0.028). The majority of long-term breast cancer survivors who received taxane-based chemotherapy reported CIPN symptoms; obesity was a significant risk factor. Those with CIPN also reported increased psychological distress and falls. Interventions need to target CIPN and comorbid psychological symptoms, and incorporate fall prevention strategies for aging breast cancer survivors.

/pdf/long-term-chemotherapy-induced-peripheral-neuropathy-among-37066moje8.pdf

Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition resulting from chemotherapy for cancer. Severe acute CIPN may require chemotherapy dose reduction or cessation. There is no effective CIPN prevention strategy; treatment of established chronic CIPN is limited, and the prevalence of CIPN is not known. Here we used a systematic review to identify studies reporting the prevalence of CIPN. We searched Embase, Medline, CAB Abstracts, CINAHL, PubMed central, Cochrane Library, and Web of Knowledge for relevant references and used random-effects meta-regression to estimate overall prevalence. We assessed study quality using the CONSORT and STROBE guidelines, and we report findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. We provide a qualitative summary of factors reported to alter the risk of CIPN. We included 31 studies with data from 4179 patients in our analysis. CIPN prevalence was 68.1% (57.7-78.4) when measured in the first month after chemotherapy, 60.0% (36.4-81.6) at 3months and 30.0% (6.4-53.5) at 6months or more. Different chemotherapy drugs were associated with differences in CIPN prevalence, and there was some evidence of publication bias. Genetic risk factors were reported in 4 studies. Clinical risk factors, identified in 4 of 31 studies, included neuropathy at baseline, smoking, abnormal creatinine clearance, and specific sensory changes during chemotherapy. Although CIPN prevalence decreases with time, at 6months 30% of patients continue to suffer from CIPN. Routine CIPN surveillance during post-chemotherapy follow-up is needed. A number of genetic and clinical risk factors were identified that require further study.

/pdf/incidence-prevalence-and-predictors-of-chemotherapy-induced-18kadm6ckh.pdf

Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

From bench to bedside: a case of rapid reversal of bortezomib-induced neuropathic pain by the TRPM8 activator, menthol.

From Bench to Bedside : A Case of Rapid Reversal of Bortezomib-Induced Neuropathic Pain by the TRPM8 Activator, Menthol. Authors' reply

31 Chemotherapy-induced Q4 peripheral neuropathy (CIPN) is a disabling pain condition resulting from chemo32 therapy for cancer. Severe acute CIPN may require chemotherapy dose reduction or cessation. There is no 33 effective CIPN prevention strategy; treatment of established chronic CIPN is limited, and the prevalence 34 of CIPN is not known. Here we used a systematic review to identify studies reporting the prevalence of 35 CIPN. We searched Embase, Medline, CAB Abstracts, CINAHL, PubMed central, Cochrane Library, and 36 Web of Knowledge for relevant references and used random-effects meta-regression to estimate overall 37 prevalence. We assessed study quality using the CONSORT and STROBE guidelines, and we report findings 38 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. 39 We provide a qualitative summary of factors reported to alter the risk of CIPN. We included 31 studies 40 with data from 4179 patients in our analysis. CIPN prevalence was 68.1% (57.7–78.4) when measured 41 in the first month after chemotherapy, 60.0% (36.4–81.6) at 3 months and 30.0% (6.4–53.5) at 6 months 42 or more. Different chemotherapy drugs were associated with differences in CIPN prevalence, and there 43 was some evidence of publication bias. Genetic risk factors were reported in 4 studies. Clinical risk fac44 tors, identified in 4 of 31 studies, included neuropathy at baseline, smoking, abnormal creatinine clear45 ance, and specific sensory changes during chemotherapy. Although CIPN prevalence decreases with 46 time, at 6 months 30% of patients continue to suffer from CIPN. Routine CIPN surveillance during post47 chemotherapy follow-up is needed. A number of genetic and clinical risk factors were identified that 48 require further study. 49 2014 The Authors. Published by Elsevier B.V. on behalf of International Association for the Study of 50 Pain. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ 51 by-nc-nd/3.0/).

Leslie A. Colvin

Papers

Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

From bench to bedside: a case of rapid reversal of bortezomib-induced neuropathic pain by the TRPM8 activator, menthol.

From Bench to Bedside : A Case of Rapid Reversal of Bortezomib-Induced Neuropathic Pain by the TRPM8 Activator, Menthol. Authors' reply

Incidence, Prevalence and Predictors of Chemotherapy Induced Peripheral Neuropathy