The serotonin receptor 2A (HTR2A) rs6313 variant is associated with higher ongoing pain and signs of central sensitization in neuropathic pain patients

Abstract

Background The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. Methods At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.‐1438G > A (rs6311) and c.102C > T (rs6313). Genotype‐related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. Results There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (−0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p < .001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. −0.34 ± 0.23 p = .002; MPS, +0.66 ± 0.17 vs. −0.09 ± 0.23, p = .009) and ongoing pain was increased by 30%. Conclusions The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. Significance This article presents new insights into serotonin receptor 2A‐mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism‐based therapies.

Interplay between genetics and lifestyle on pain susceptibility in women with fibromyalgia: the al-Ándalus project

“…In FM, abnormalities in the serotoninergic system are present [ 37 ] and selective serotonin reuptake inhibitors are effective for treating pain in some patients [ 38 ]. Therefore, the rs6313 variant in the HTR2A gene may be involved in pain-related outcomes, which is consistent with our findings [ 39 , 40 ].…”

Estrogen exacerbates the nociceptive effects of peripheral serotonin on rat trigeminal sensory neurons

“…One of the several excitatory receptors of 5HT in the periphery, the 5HT 2A receptor, has been implicated in several pain conditions including irritable bowel syndrome, fibromyalgia, headache and migraine, and temporomandibular joint disorder (TMD) ( Sugiuar et al, 2004 ). In humans, a specific single nucleotide variation in the 5HT 2A receptor, rs6313, is associated with pinprick hyperalgesia ( Sachau et al, 2021 ) and the T/T genotype of the T102C polymorphism is associated with low pain thresholds in fibromyalgia patients ( Gürsoy et al, 2001 ). In rodents, the 5HT 2A receptor is involved in thermal allodynia and mechanical hypersensitivity associated with neuropathy and treatment with a 5HT 2A antagonist attenuated pain behaviors ( Thibault et al, 2008 ).…”

Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial

“…Taken together these results emphasize that the mechanistic study successfully enrolled the targeted mechanical (not thermal) hyperalgesia pain phenotype of patients within these studies. This patient subgroup is most likely to harbour a central sensitization aspect, for which punctate hyperalgesia and dynamic mechanical allodynia are hallmark signs [ 1 , 34 , 35 ], associated with increased ongoing pain [ 36 ].

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“…It is, however, also possible that reduction in stimulus-evoked pain in some patients does not fully translate into reduction of their spontaneous pain. Although we were recently able to show in a genotype–phenotype association study that more punctate hyperalgesia predicted stronger ongoing pain the correlation still remained low [ 36 ]. A disconnect between spontaneous and stimulus evoked neuropathic pain has been illustrated elsewhere [ 39 , 40 ].…”