Excitatory and inhibitory responses in the brain to experimental pain: A systematic review of MR spectroscopy studies.

BACKGROUND: The role of the brain in processing pain has been extensively investigated using various functional imaging techniques coupled with well controlled noxious stimuli. Studies applying experimental pain have also used proton magnetic resonance spectroscopy (1H-MRS). The advantage of MRS compared to other techniques is the capacity to non-invasively examine metabolites involved in neurotransmission of pain, including glutamate, γ-aminobutyric acid (GABA), glutamate â€‹+ â€‹glutamine (Glx), and glutamine. OBJECTIVE: To systematically review MRS studies used in the context of studying experimental pain in healthy human participants. DATA SOURCES: PubMed, Ovid Medline, and Embase databases were searched using pre-specified search terms. ELIGIBILITY CRITERIA: Studies investigating glutamate, GABA, Glx and/or glutamine in relation to experimental pain (e.g., heat) in healthy participants via MRS. APPRAISAL CRITERIA: Each study was evaluated with a modified quality criterion (used in previous imaging systematic reviews) as well as a risk of bias assessment. RESULTS: From 5275 studies, 14 met the selection criteria. Studies fell into two general categories, those examining changes in metabolites triggered by noxious stimulation or examining the relationship between sensitivity to pain and resting metabolite levels. In five (out of ten) studies, glutamate, Glx and/or glutamine increased significantly in response to experimental pain (compared to baseline) in three different brain areas. To date, there is no evidence to suggest Glx, glutamate or glutamine levels decrease, suggesting an overall effect in favour of increased excitation to pain. In addition to no changes, both increases and decreases were reported for levels of GABA+ (=GABA â€‹+ â€‹macromolecules). A positive correlation between pain sensitivity and resting glutamate and Glx levels were reported across three studies (out of three). Further research is needed to examine the relationship of GABA+ and pain sensitivity. LIMITATIONS: A major limitation of our review was a limited number of studies that used MRS to examine experimental pain. In light of this and major differences in study design, we did not attempt to aggregate results in a meta-analysis. As for the studies we reviewed, there was a limited number of brain areas were examined by studies included in our review. Moreover, the majority of studies included lacked an adequate control condition (i.e., non-noxious stimulation) or blinding, which represent a major source of potential bias. CONCLUSION: MRS represents a promising tool to examine the brain in pain, functionally, and at rest with support for increased glutamate, glutamine and Glx levels in relation to pain. IMPLICATIONS: Resting and functional MRS should be viewed as complementary to existing neuroimaging techniques, and serve to investigate the brain in pain. Systematic review registration number- CRD42018112917.

Effectiveness of High-Frequency Electrical Stimulation Following Sensitization With Capsaicin.

UNLABELLED: Although nonnoxious, high-frequency electrical stimulation applied segmentally (ie, conventional transcutaneous electrical nerve stimulation [TENS]) has been proposed to modulate pain, the mechanisms underlying analgesia remain poorly understood. To further elucidate how TENS modulates pain, we examined evoked responses to noxious thermal stimuli after the induction of sensitization using capsaicin in healthy volunteers. We hypothesized that sensitization caused by capsaicin application would unmask TENS analgesia, which could not be detected in the absence of sensitization. Forty-nine healthy subjects took part in a series of experiments. The experiments comprised the application of topical capsaicin (.075%) on the left hand in the C6 dermatome, varying the location of TENS (segmental, left C6 dermatome, vs extrasegmental, right shoulder), and assessing rating of perception (numeric rating scale: 0-10) and evoked potentials to noxious contact heat stimuli. The extrasegmental site was included as a control condition because previous studies indicate no analgesic effect to remote conventional TENS. Conventional TENS had no significant effect on rating or sensory evoked potentials in subjects untreated with capsaicin. However, segmental TENS applied in conjunction with capsaicin significantly reduced sensation to noxious thermal stimuli following a 60-minute period of sensitization. PERSPECTIVE: The study indicates that sensitization with capsaicin unmasks the analgesic effect of conventional TENS on perception of noxious contact heat stimuli. Our findings indicate that TENS may be interacting segmentally to modulate distinct aspects of sensitization, which in turn results in analgesia to thermal stimulation.