Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

Andreas Binder,Janne Gierthmühlen,Denisa May,Christian Maihöfner,Jihong Zhu,Nurcan Üçeyler,Achim Berthele,Volker Huge,Ingolf Cascorbi,Sierk Haenisch,Andrea Scherens,Christoph Maier,Ralf Baron,Thomas R Tölle,Mike Ufer,Helmut Richter,Herta Flor,Gunnar Wasner,Walter Magerl,Frank Faltraco,Rolf‐Detlef Treede ,R Rolke

doi:10.1371/journal.pone.0017387

Abstract

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.

Highlights

Neuropathic pain arises after lesions or diseases of the somatosensory nervous system and involves multiple somatosensory phenomena
In this study we describe the results of an association analysis of polymorphisms in TRP vanilloid 1 (TRPV1), TRP melastin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) genes with somatosensory signs of neuropathic pain patients
Association of transient receptor potential (TRP) gene variants to quantitative sensory testing (QST) Z-scores First, within the group of patients who suffered from paradoxical heat sensation (PHS) heterozygous and homozygous carriers of the TRPA1 710G.A variant were significantly underrepresented as compared to neuropathic pain patients without PHS (Fig. 1)

Summary

Introduction

Neuropathic pain arises after lesions or diseases of the somatosensory nervous system and involves multiple somatosensory phenomena. The understanding of the molecular basis of neuropathic pain has been expanded by the cloning and characterization of the transient receptor potential (TRP) family of voltage-gated ion channels Among these the TRP vanilloid 1 (TRPV1), TRP melastin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) subfamilies have been found to play important roles in transduction and sensitisation in primary afferent somatosensory neurons [4]. TRPV1 is involved in the transduction of noxious heat and a receptor for capsaicin, mediating heat hyperalgesia after stimulation with this hot chilli constituent [5] It is expressed on small diameter nociceptive neurons, likely to be C-fibers [6]. On the peptide level it is 20% homologous to TRPV1 and is co-expressed with TRPV1 in a subpopulation of unmyelinated nociceptive neurons suggesting an important role in nociception [9]

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