We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain.
Repetitive transcranial magnetic stimulation (rTMS) has had partly incongruous effects on cutaneous sensibility, and there are no systematic studies on the effects of rTMS on facial sensory function. We assessed modulation of thermal sensitivity of facial skin in healthy subjects by navigated rTMS (10 Hz), enabling accurate localization of predefined cortical targets: right primary motor cortex (M1) of facial muscles, primary somatosensory cortex (S1) representing the cheek, dorsolateral prefrontal cortex (DLPFC), and secondary somatosensory cortex (S2); the control site was occipital cortex (OCC). Applying signal detection theory, we investigated whether the rTMS-induced changes in heat-pain threshold (HPT) relate to an alteration in the subject's discriminative capacity (sensory factor) or response criterion (non-sensory factor). HPT increased after stimulation of S2, but also 45 min after stimulation of DLPFC and OCC. S2 stimulation produced the most effective and long-lasting heat hypoalgesia that was associated with a decrease in discriminative capacity and an increase in response criterion. Cold-pain threshold was elevated after S2 stimulation only in men. Stimulation of M1 decreased capacity to discriminate painful heat without influencing HPT; there was large interindividual variation in rTMS effects in the M1/S1 areas. Detection threshold for innocuous warming rose similarly after rTMS of M1, S1, DLPFC, S2 and OCC, whereas sensibility to innocuous cooling transiently improved after rTMS of S1. The results indicate that rTMS applied anatomically accurately to S2 may produce analgesia in the face via multiple mechanisms, partly depending on gender, and involving decreased discriminative capacity and increased response criterion.
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