Caffeine Consumption Influences Lidocaine Action via Pain-Related Voltage-Gated Sodium Channels: An In Vivo Animal Study

Several factors might influence the duration and efficiency of local anesthesia. This study investigates the effect of habitual caffeine intake on lidocaine action and explores the potential involvement of voltage-gated sodium channels in the interaction effect. Wistar rats were divided into four groups: (i) control (Ctrl), (ii) lidocaine intraplantar injection (LIDO), (iii) habitual caffeine intake (CAF), and (iv) lidocaine intraplantar injection and habitual caffeine intake (LIDO + CAF). Behavioral assessments, consisting of a paw pressure test for mechanical pressure sensation and a paw withdrawal latency test for thermal pain sensation, were performed at 0, 30, 60, and 90 minutes following lidocaine injection and after 10, 11, and 12 weeks of CAF intake. Pressure sensation was significantly reduced in the LIDO + CAF group compared with the control group. Moreover, the LIDO + CAF group exhibited reduced sensation compared to LIDO alone group. The LIDO + CAF combination exerted a synergistic effect at 30 and 60 minutes compared with the control. This synergistic effect was noted at 60 minutes (11 weeks of CAF intake) and at 30 minutes (12 weeks of CAF intake) compared with LIDO alone. Augmented thermal pain-relieving effects were observed in the LIDO + CAF group at all weeks compared to the control group and at 10 weeks compared to LIDO alone group. The molecular analysis of dorsal root ganglia suggested that CAF upregulated the mRNA expression of the Nav1.3, Nav1.7, and Nav1.8 sodium channel subtypes. Chronic caffeine consumption potentiates the local anesthetic action of lidocaine in an experimental animal model through mechanisms that involve the upregulation of voltage-gated sodium channels in the dorsal root ganglia.

Robotic Stroking on the Face and Forearm: Touch Satiety and Effects on Mechanical Pain

Background: Slow stroking touch is generally perceived as pleasant and reduces thermal pain. However, the tactile stimuli applied tend to be short-lasting and typically applied to the forearm. This study aimed to compare the effects of a long-lasting brushing stimulus applied to the facial region and the forearm on pressure pain thresholds (PPTs) taken on the hand. Outcome measurements were touch satiety and concurrent mechanical pain thresholds of the hand.Methods: A total of 24 participants were recruited and randomized to receive continuous stroking, utilizing a robotic stimulator, at C-tactile (CT) favorable (3 cm/s) and non-favorable (30 cm/s) velocities applied to the right face or forearm. Ratings of touch pleasantness and unpleasantness and PPTs from the hypothenar muscle of the right hand were collected at the start of stroking and once per minute for 5 min.Results: A reduction in PPTs (increased pain sensitivity) was observed over time (P < 0.001). However, the increase in pain sensitivity was less prominent when the face was stroked compared to the forearm (P = 0.001). Continuous stroking resulted in a significant interaction between region and time (P = 0.008) on pleasantness ratings, with a decline in ratings observed over time for the forearm, but not on the face. Unpleasantness ratings were generally low.Conclusion: We observed touch satiety for 5 min of continuous robotic brushing on the forearm confirming previous studies. However, we did not observe any touch satiety for brushing the face. Mechanical pain sensitivity, measured in the hand, increased over the 5-min period but less so when paired with brushing on the face than with brushing on the forearm. The differential effects of brushing on the face and forearm on touch satiety and pain modulation may be by the differences in the emotional relevance and neuronal pathways involved.

Race-Related Differences Between and Within Sex to Experimental Thermal Pain in Middle and Older Adulthood: An Exploratory Pilot Analysis

This brief report details a pilot analysis conducted to explore racial differences in pain sensitivity and unpleasantness between cognitively healthy Black and White adults, stratified by sex. A total of 24 cognitively healthy adults (12 Black and 12 White) from two completed studies were matched by age and sex, and divided into two groups based on race. Stratified analyses by sex demonstrated that Black females reported experiencing pain intensity ratings of all three intensity sensations at lower temperatures than White females. These findings will inform future research studies to determine if these results hold true in a fully-powered sample and should include mixed methodologies, incorporating neuroimaging data to further assess this phenomenon. Improving pain assessment and management across racial/ethnic groups will help healthcare providers such as nurses and physicians to ensure optimal quality of life for all.

Altered Neurotransmitter Ratio in the Prefrontal Cortex is Associated with Pain in Fibromyalgia Syndrome

The central mechanisms underlying fibromyalgia syndrome (FMS) remain undetermined. The dorsolateral prefrontal cortex (DLPFC) is particularly relevant to FMS because it is implicated in cognitive, affective, and top-down pain regulation. Imbalances in excitatory (Glutamate) and inhibitory (Gamma aminobutyric acid; GABA) neurochemicals may play a critical role in the pathophysiology of the condition and more generally in homeostatic function within cortical circuits. Although the balance of excitation and inhibition are intrinsically linked no investigations to date have investigated the E/I ratio in FMS. Thus, the primary objective of this study was to determine whether the E/I ratio in the DLPFC is altered in participants with FMS compared to healthy controls using magnetic resonance spectroscopy. Additionally, we examined the relationship between E/I ratio and pain metrics. We hypothesized that the E/I ratio within the DLPFC would be altered in participants with FMS compared to controls and, secondly, that E/I ratio would be associated with both clinical pain and thermal pain sensitivity. The Brief Pain Inventory (BPI) self-assessment was used to evaluate pain severity and impact on physical functioning and acute pain sensitivity was determined via quantitative sensory testing to define thermal (heat) pain threshold and tolerance. Our results revealed an elevation in the E/I ratio in FMS compared to controls. A positive relationship between E/I ratio and thermal pain sensitivity measures was identified in the FMS cohort. Collapsing across groups, there was a positive relationship between E/I ratio and BPI score. These findings suggest that dysfunction in the balance between excitation and inhibition within cognitive brain circuitry may play a role in pain processing in FMS.

Heat Emitting Damage in Skin: A Thermal Pathway for Mechanical Algesia

Mechanical pain (or mechanical algesia) can both be a vital mechanism warning us for dangers or an undesired medical symptom important to mitigate. Thus, a comprehensive understanding of the different mechanisms responsible for this type of pain is paramount. In this work, we study the tearing of porcine skin in front of an infrared camera, and show that mechanical injuries in biological tissues can generate enough heat to stimulate the neural network. In particular, we report local temperature elevations of up to 24°C around fast cutaneous ruptures, which shall exceed the threshold of the neural nociceptors usually involved in thermal pain. Slower fractures exhibit lower temperature elevations, and we characterise such dependency to the damaging rate. Overall, we bring experimental evidence of a novel—thermal—pathway for direct mechanical algesia. In addition, the implications of this pathway are discussed for mechanical hyperalgesia, in which a role of the cutaneous thermal sensors has priorly been suspected. We also show that thermal dissipation shall actually account for a significant portion of the total skin's fracture energy, making temperature monitoring an efficient way to detect biological damages.

Test-retest reliability of an adaptive thermal pain calibration procedure in healthy volunteers

Quantitative sensory testing (QST) allows researchers to evaluate associations between noxious stimuli and acute pain in clinical populations and healthy participants. Despite its widespread use, our understanding of QST’s reliability is limited, as reliability studies have used small samples and restricted time windows. We examined the reliability of pain ratings in response to noxious thermal stimulation in 171 healthy volunteers (n = 99 female, n = 72 male) who completed QST on multiple visits ranging from 1 day to 952 days between visits. On each visit, participants underwent an adaptive pain calibration in which they experienced 24 heat trials and rated pain intensity after stimulus offset on a 0-10 Visual Analog Scale. We used linear regression to determine pain threshold, pain tolerance, and the correlation between temperature and pain for each session and examined the reliability of these measures. Threshold and tolerance were moderately reliable (Intra-class correlation [ICC]=0.66 and 0.67, respectively; p<.001), whereas temperature-pain correlations had low reliability (ICC=0.23). In addition, pain tolerance was significantly more reliable in female participants than male participants, and we observed similar trends for other pain sensitive measures. Our findings indicate that threshold and tolerance are largely consistent across visits, whereas sensitivity to changes in temperature vary over time and may be influenced by contextual factors.

Zona Incerta Stimulation Likely to be Particularly Effective in Central Post-Stroke Pain.

Lu et al. (2021) recently reported that deep brain stimulation (DBS) of the zona incerta (ZI) selectively modulates thermal pain in humans. This important finding has implications for the mechanism and treatment of neuropathic pain and particularly, as I explore in this paper, central post-stroke pain (CPSP). The condition, now termed CPSP, was first described in 1906 by Dejerine and Roussy, who noted that “nothing offers solace to the patient whose feeling are sometimes intolerable”. Over a century later CPSP remains a difficult, often refractory, condition to treat. One that can even drive sufferers to suicide.