**Author details**

**17. Genetic and environmental determinants of pain susceptibility**

18 Peripheral Neuropathy - A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder

severity, progression, duration, or presentation.

**18. Conclusion**

worldwide impact of neuropathic pain.

**Acknowledgements**

A major challenge in treating neuropathic pain is the heterogeneity of disease pathogenesis within an individual etiological classification. Patients with seemingly identical diseases may experience completely different neuropathic pain phenotypes, possibly due to genetic and environmental variation. A holistic approach to treating neuropathic pain, therefore, will require identification of risk or determinant factors that may play a role in neuropathic pain

Although there are major obstacles to studying the genetics of pain in humans, a few potential biomarkers have been identified [96]. A candidate gene association study, which compares allele frequencies between cohorts of patients with and without a particular trait, has yielded evidence that a polymorphism in catechol-O-methyltransferase (COMT) is associated with temporomandibular joint disorder [97, 98]. Other similar studies have identified alleles for the µ-opioid receptor 1 (OPRM1) [99] and the melanocortin-1 receptor (MCR1) [100] as potential determinants of sensitivity to opioid induced analgesia. A separate approach to identifying genetic determinants of pain biology uses rodent models and has also yielded promising results. Using this method, Tegeder et. al. identified a haplotype for the enzyme GTP cyclo‐ hydrolase 1 (GCH1), the rate limiting enzyme in the synthesis of tetrahydrobiopterin (BH4) [101]. BH4 is an important cofactor in the synthesis of serotonin, catecholamines, and all nitric

Neuropathic pain is a major source of physical and mental disability worldwide. It is associated with severe societal and individual psychosocial burden and will continue to be a major health concern until more effective treatments emerge. One of the biggest barriers to successful management of neuropathic pain has been the lack of understanding in the underlying pathophysiology that produces a pain phenotype. To that end, significant progress has been made in basic science research. From the discovery of the nociceptor and individual ion channel transducers to the mapping of pain representation in the brain, a foundational understanding has been laid. As we continue to build on this foundation, it is essential that strong communication exists between the laboratory and the clinic in order to ensure effective translation. With optimism we suggest that this could lead to better patient care and lessen the

The authors are supported by National Institutes of Health grants NIDCR-DE020868 (LET), NCI-CA37404 (CLL and LET), and American Cancer Society- New Investigator Award (LET).

We would like to thank Maja Radulovic for assistance in creating the figures.

oxide synthases [101] and plays a role in the development of chronic pain [96].

Emily A. Ramirez1 , Charles L. Loprinzi2 , Anthony Windebank1,3,4 and Lauren E. Ta1,3,4\*

\*Address all correspondence to: Ta.lauren@mayo.edu

1 Molecular Neuroscience Program, Graduate School, Mayo Clinic, College of Medicine, Ro‐ chester, Minnesota, USA

2 Division of Medical Oncology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA

3 Department of Neurology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA

4 Department of Neuroscience, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA
