Capsaicin Pain Research Articles

Pain modulates brain potentials and behavioral responses to unfairness.

Pain may initially contribute to the evolution of moral decision-making as it elicits avoidance behavior. The current study aims to support this perspective by conducting a behavioral study to investigate whether pain leads to a self-oriented tendency, and an exploratory electroencephalogram (EEG) study to examine how pain affects moral decision-making. In Experiment 1, 34 participants were recruited and treated with both capsaicin (pain condition) and hand cream (control condition) in separate days. After treatment, they were asked to complete a third-party punishment task. Results showed that pain increased punishment and decreased compensation towards unfair allocations in the task. In Experiment 2, 68 participants with either pain or control treatment participated in an EEG experiment. It revealed that pain enlarged the disparity of late positive potential (LPP) between fair and unfair situations, suggesting that individuals in pain may exert more cognitive effort when facing unfair allocations. Meanwhile pain did not affect the early components P2 and the medial frontal negativity, indicating unaffected attentional or anticipatory responses towards unfairness. It demonstrates that pain can effectively modulate responses to unfairness, manifesting as a self-oriented approach with negative consequences for others. It suggests a potential evolutionary impact of pain on moral decisions.

Synthesis of diversely substituted pyridin-2(1H)-ones and in vivo evaluation of their anti-allodynic effect on cutaneous inflammatory mechanical allodynia.

A series of 3,5-disubtituted pyridin-2(1H)-ones was synthesized. As part of a structure-activity relationship study performed in this series, structural modifications were based on 3-(indol-4-yl)-5-(pyridin-4-ylamino)pyridin-2(1H)-one B, which exhibited a potent anti-allodynic effect in a rat model of inflammatory pain. In this study, new compounds were assessed for their ability to inhibit cutaneous mechanical allodynia in rats by using the capsaicin pain model. Compound 36, a 2-methoxypyridine derivative, yielded the most promising outcome, demonstrating an enhanced analgesic effect.

Temporal dynamics of electroencephalographic microstates during sustained pain.

Brain dynamics can be modeled by a sequence of transient, nonoverlapping patterns of quasi-stable electrical potentials named "microstates." While electroencephalographic (EEG) microstates among patients with chronic pain remained inconsistent in the literature, this study characterizes the temporal dynamics of EEG microstates among healthy individuals during experimental sustained pain. We applied capsaicin (pain condition) or control (no-pain condition) cream to 58 healthy participants in different sessions and recorded resting-state EEG 15min after application. We identified 4 canonical microstates (A-D) that are related to auditory, visual, salience, and attentional networks. Microstate C had less occurrence, as were bidirectional transitions between microstate C and microstates A and B during sustained pain. In contrast, sustained pain was associated with more frequent and longer duration of microsite D, as well as more bidirectional transitions between microstate D and microstates A and B. Microstate D duration positively correlated with intensity of ongoing pain. Sustained pain improved global integration within microstate C functional network, but weakened global integration and efficiency within microstate D functional network. These results suggest that sustained pain leads to an imbalance between processes that load on saliency (microstate C) and processes related to switching and reorientation of attention (microstate D).

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Ongoing pain facilitates emotional decision-making behaviors

Emotion toward anticipated and actual outcomes acts as a vital signal on emotional decision-making, and the Iowa Gambling Task (IGT) can mimic this decision-making process. Pain can impair emotional decision-making behaviors because it captures attention and distracts from the task at hand. Alternatively, pain may facilitate emotional decision-making behaviors by prompting alertness and mobilizing cognitive resources to maximize rewards. The present study investigated the influence of ongoing pain on emotional decision-making behaviors using the IGT. Our study recruited two groups of participants and applied capsaicin (pain group) or control cream (control group) to their forearms. We then compared performances and selections between the pain and control groups. The results revealed that participants successfully learned the required adaptive selection strategy as the task progressed. The study observed a tendency toward optimal choices for both groups under the condition of frequent–small losses. However, we observed a disadvantageous preference for the control group, but not the pain group, when faced with choices with infrequent but large losses. The study implies that a distressing pain experience motivates individuals to adjust goal-directed behaviors to maximize their rewards in a task. Thus, the finding suggests that ongoing pain facilitates emotional decision-making behaviors.

An Efficacy of Photobiomodulation of 850 nm on Pain Reduction in a Human Oral Capsaicin Pain Model.

Objective: The aim of this clinical trial was to evaluate the efficacy of photobiomodulation (PBM) to reduce oral pain initiated by capsaicin. Background: PBM has been used for pain reduction in oral regions; however, its clinical efficacy to alleviate burning sensations is still unknown. Methods: This clinical study was divided into two phases. There were 10 subjects in each phase. In Phase I, the burning sensation was stimulated using 0.05% in 95% ethanol capsaicin (prepared by the Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand) on filter paper and recorded with a 10-cm horizontal visual analog scale (VAS) every 1 min until the subject experienced no more pain. The area under the curve (AUC) of the graph between VAS and time was calculated. The washout period was 24 h. In Phase II, a crossover clinical trial was conducted in subjects who received the pain model as stated. Four interventions were included: (1) PBM before & after pain stimulation, (2) PBM before pain stimulation, (3) PBM after pain stimulation, and (4) Placebo. For PBM intervention, a single exposure of 850 nm Laser (AsGaAl; TOP 250 Soft Laser, Berkmed Medikal, distributed by Medical Innovation-MI, Istanbul, Turkey) with 0.10 cm2 spot size laser probe continuous wave at 1 W/cm2 and 30 J/cm2 for 30 sec was used. Results: In Phase I, there was no statistically significant difference (p = 0.09) between the average AUC of day 1 [55.63 (23.38)] and day 2 [48.99 (27.20)]. In phase II, there was no statistical difference (p = 0.20) of the average AUC among the interventions and the placebo; group 1 [56.24 (30.11)], group 2 [45.46 (45.46)], group 3 [64.15 (32.89)], and group 4 [58.59 (30.16)]. Conclusions: The human capsaicin model was suitable for a crossover design clinical trial. The PBM used in this study did not reduce oral burning sensations from capsaicin.

Chiropractic Spinal Manipulation Prevents Secondary Hyperalgesia Induced by Topical Capsaicin in Healthy Individuals.

Background and Aims: Spinal manipulation (SM) is currently recommended for the management of back pain. Experimental studies indicate that the hypoalgesic mechanisms of SM may rely on inhibition of segmental processes related to temporal summation of pain and, possibly, on central sensitization, although this remains unclear. The aim of this study was to determine whether experimental back pain, secondary hyperalgesia, and pain-related brain activity induced by capsaicin are decreased by segmental SM.Methods: Seventy-three healthy volunteers were randomly allocated to one of four experimental groups: SM at T5 vertebral level (segmental), SM at T9 vertebral level (heterosegmental), placebo intervention at T5 vertebral level, or no intervention. Topical capsaicin was applied to the area of T5 vertebra for 40 min. After 20 min, the interventions were administered. Pressure pain thresholds (PPTs) were assessed outside the area of capsaicin application at 0 and 40 min to examine secondary hyperalgesia. Capsaicin pain intensity and unpleasantness were reported every 4 min. Frontal high-gamma oscillations were also measured with electroencephalography.Results: Pain ratings and brain activity were not significantly different between groups over time (p > 0.5). However, PPTs were significantly decreased in the placebo and control groups (p < 0.01), indicative of secondary hyperalgesia, while no hyperalgesia was observed for groups receiving SM (p = 1.0). This effect was independent of expectations and greater than placebo for segmental (p < 0.01) but not heterosegmental SM (p = 1.0).Conclusions: These results indicate that segmental SM can prevent secondary hyperalgesia, independently of expectations. This has implications for the management of back pain, particularly when central sensitization is involved.

Novel (‒)-carvone derivatives as potential anticonvulsant and analgesic agents

Novel hydrazones based on (‒)-carvone were synthesized via condensation of terpenoid with 4-R-phenoxyacetic acid hydrazides. The structure of target compounds was established by FT-IR, Raman, 1H-NMR and 13C-NMR spectral analysis, FAB/ESI mass spectrometry. (‒)-Carvone hydrazones were proven to exist as Z/E geometrical isomers about C = N bond using ion mobility-tandem mass spectrometry (IM-MS/MS). Single crystal X-ray diffraction study was applied to determine molecular and crystal structure of compound 3e. Hydrazones 3a-3e were evaluated as potential anticonvulsant agents after their oral administration against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in mice. Analgesic activity of compounds was investigated by topical application on models of capsaicin and AITC-induced pain. The present findings indicate that (‒)-carvone derivatives afforded seizure protection both at short (1 h) and long (24 h) time period by blocking electroshock- and chemical-induced convulsions. Hydrazones binding to TRPA1/TRPV1 ion channels was proposed as possible mechanism explaining significant analgesic effect of compounds.

Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats.

Spontaneous pain after surgical incision is a significant problem for most post-operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non-opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post-operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre-operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30min or 1week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri-incisional tissue biopsies. Intraplantar administration of capsaicin 30min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2weeks post-incision, at a time when no recovery of epidermal innervation is observed. Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision-induced pain behaviours and reduced epidermal innervation around the incision site. The long-lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours. Pre-operative capsaicin infiltration attenuated spontaneous pain-like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long-lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre- or intra-operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post-operative pain and reduce the need for opioids during recovery.

Temporal aspects of endogenous pain modulation during a noxious stimulus prolonged for 1 day.

This study investigated (a) if a prolonged noxious stimulus (24-hr topical capsaicin) in healthy adults would impair central pain inhibitory and facilitatory systems measured as a reduction in conditioned pain modulation (CPM) and enhancement of temporal summation of pain (TSP) and (b) if acute pain relief or exacerbation (cooling and heating the capsaicin patch) during the prolonged noxious stimulus would affect central pain modulation. Twenty-eight participants (26.2±1.0years; 12 women) wore a transdermal 8% capsaicin patch on the forearm for 24hr. Data were collected at baseline (Day 0), 1hr, 3hr, Day 1 (post-capsaicin application) and Day 3/4 (post-capsaicin removal) that included capsaicin-evoked pain intensity, heat pain thresholds (HPTs), TSP (10 painful cuff pressure stimuli on leg) and CPM (cuff pressure pain threshold on the leg prior vs. during painful cuff pressure conditioning on contralateral leg). After 3hr, cold (12°C) and heat (42°C) stimuli were applied to the capsaicin patch to transiently increase and decrease pain intensity. Participants reported moderate pain scores at 1hr (2.5±2.0), 3hr (3.7±2.4), and Day 1 (2.4±1.8). CPM decreased 3-hr post-capsaicin (p=.001) compared to Day 0 and remained diminished while the capsaicin pain score was reduced (0.4±0.7, p<.001) and increased (6.6±2.2, p<.001) by patch cooling and heating. No significant differences occurred for CPM during patch cooling or heating compared to initial 3HR; however, CPM during patch heating was reduced compared with patch cooling (p=.01). TSP and HPT did not change. This prolonged experimental pain model is useful to provide insight into subacute pain conditions and may provide insight into the transition from acute to chronic pain. During the early hours of a prolonged noxious stimulus in healthy adults, CPM efficacy was reduced and did not recover by temporarily removing the ongoing pain indicating a less dynamic neuroplastic process.

A data science approach to the selection of most informative readouts of the human intradermal capsaicin pain model to assess pregabalin effects.

Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin-based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo-controlled, randomized cross-over study, seven different pain-related readouts were acquired in 16 healthy individuals before and after oral administration of 300mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain-related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.

A randomised, double-blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial.

Preclinical studies suggest that type 2 hyperpolarization-activated cyclic nucleotide gated ion channels (HCN2) are necessary for neuropathic pain. This trial assessed the influence of ivabradine, a nonselective HCN channel blocker, on capsaicin-induced hyperalgesia and pain in healthy human subjects. An enriched population comprising subjects who developed >20 cm of punctate hyperalgesia from topical capsaicin (0.5% cream applied onto 9 cm area) was identified. These subjects then received ivabradine (15 mg) or placebo 1 hour before capsaicin application in randomly allocated order in a crossover study. The forearm site for capsaicin alternated with each application of the cream. The interval of time from screening to the first and to the second treatment visits was at least 3 and 5 weeks, respectively, to minimize carryover effects. Fifty-five participants were screened, of which 25 completed at least 1 treatment visit. Intention-to-treat hierarchical analysis revealed no significant effects of the drug on primary trial outcome, defined as a difference in effects of placebo and ivabradine on the area of punctate hyperalgesia (ivabradine - placebo: mean = 3.22 cm, 95% confidence interval: = -4.04 to 10.48, P = 0.37). However, ivabradine caused a slowing of heart rate (difference of 10.10 beats per minute [95% confidence interval -6.48 to -13.73; P-value <0.0001]). We conclude that ivabradine lacks analgesic effects in the capsaicin pain model at a dose that caused appreciable slowing of heart rate and, hence, is unlikely to prove a useful analgesic in humans. More selective drugs are required to establish a role of HCN2 for pain in humans.

Mannitol Cream for Pain Control, a Chart Review

POSTER ABSTRACTIntroduction/Aim: topical mannitol was shown to down regulate the capsaicin pain receptor. How effective would it be for pain control in clinical practice?Methods: a chart review of 235 patients who received a 30% mannitol, cream for pain. Each patient used the cream on whatever part of their body was painful. Their chart contained a data sheet with: date, time, numeric pain score 0 = no pain to 10 = worst imaginable pain before and 30 minutes after application, minutes until relief, duration of relief.Results: Of the 235 participants, there were 366 different areas of the body that were treated. The average pain relief was 50.8% (SD 29.8), median 52.94%. Areas of the body experiencing over 60% relief were the thumb and fingers, wrists, thigh, leg and knee (where the affected nerves are closest to the skin surface). The following areas had pain relief scores between 50% and 59%: foot, neck, arm, hip and back. 7 people developed a transient rash in the area where the cream was being applied, which resolved when cream use was stopped.Discussion/Conclusions: The average pain relief for mannitol cream was 50.8% whereas for narcotics it is 36%, for oral or topical NSAIDS it is 23% and acetaminophen it is 13%. This is, however, only a retrospective observational study, not a randomized placebo-controlled study so it is, subject to the placebo effect. Topical mannitol may prove useful in providing pain relief. It needs to be tested in a randomized, placebo-controlled study which is currently underway.

Multicenter assessment of quantitative sensory testing (QST) for the detection of neuropathic-like pain responses using the topical capsaicin model

ABSTRACT Background The use of quantitative sensory testing (QST) in multicenter studies has been quite limited, due in part to lack of standardized procedures among centers. Aim The aim of this study was to assess the application of the capsaicin pain model as a surrogate experimental human model of neuropathic pain in different centers and verify the variation in reports of QST measures across centers. Methods A multicenter study conducted by the Quebec Pain Research Network in six laboratories allowed the evaluation of nine QST parameters in 60 healthy subjects treated with topical capsaicin to model unilateral pain and allodynia. The same measurements (without capsaicin) were taken in 20 patients with chronic neuropathic pain recruited from an independent pain clinic. Results Results revealed that six parameters detected a significant difference between the capsaicin-treated and the control skin areas: (1) cold detection threshold (CDT) and (2) cold pain threshold (CPT) are lower on the capsaicin-treated side, indicating a decreased in cold sensitivity; (3) heat pain threshold (HPT) was lower on the capsaicin-treated side in healthy subjects, suggesting an increased heat pain sensitivity; (4) dynamic mechanical allodynia (DMA); (5) mechanical pain after two stimulations (MPS2); and (6) mechanical pain summation after ten stimulations (MPS10), are increased on the capsaicin-treated side, suggesting an increased in mechanical pain (P < 0.002). CDT, CPT and HPT showed comparable effects across all six centers, with CPT and HPT demonstrating the best sensitivity. Data from the patients showed significant difference between affected and unaffected body side but only with CDT. Conclusion These results provide further support for the application of QST in multicenter studies examining normal and pathological pain responses.

Synthesis and Pharmacological Properties of Novel Esters Based on Monoterpenoids and Glycine.

Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by 1H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, respectively. Glycine esters of menthol and borneol exhibited higher antinociceptive action, whereas eugenol derivative significantly suppressed the development of the inflammatory process. The mechanism of competitive binding between terpenoid esters and TRPA1/TRPV1 agonists was proposed explaining significant analgesic effect of synthesized derivatives. For an explanation of high anti-inflammatory activity, competitive inhibition between terpenoid esters and AITC for binding sites of the TRPA1 ion channel has been suggested.

Antinociceptive and anti-inflammatory effects of the methanolic stem bark extract of Antrocaryon klaineanum Pierre (Anacardiaceae) in mice and rat

Ethnopharmacological relevanceAntrocaryon klaineanum is used by traditional healers to treat many disorders including pain and inflammatory diseases. This study aimed to evaluate the analgesic and antiinflammatory activities of methanol extract of A. klaineanum in mice and rats. Materials and methodsReverse phase high-performance liquid chromatography (RP-HPLC) was performed to establish the chromatographic fingerprint and to identify various chemical components of the plant extract. The anti-nociceptive activity of methanol extract of A. klaineanum was assessed using the acetic acid-induced abdominal constriction model, formalin test, capsaicin and cinnamaldehyde induced-neurogenic pain and hot plate test. Anti-inflammatory activity was assessed on carrageenan-induced inflammation. Extract was administrated orally at 200, 400 and 600mg/kg. ResultsPhytochemical analysis indicated the presence of proanthocyanidins, phenolic acids and flavonoids. The results of anti-nociceptive and anti-inflammatory activities showed that methanol extract significantly (p<0.01) reduced the pain induced by acetic acid with an inhibition percentage of 45.49% (600mg/kg). In the formalin test, the extract also significantly (p<0.01) reduced linking time in both phase (neurogenic and inflammatory) of the test with inhibition percentage of 56.28% and 60.73% respectively at the dose of 600mg/kg. The methanol extract of A. klaineanum significantly (P<0.001) reduced neurogenic pain linking time induced by capsaicin and cinnamaldehyde by 82.54% and 75.94% at the highest dose (600mg/kg) respectively. More over the extract significantly increase the reaction time in hot plate test. In the inflammatory test, the plant extract significantly reduced the carrageen induced rat paw oedema from 30min to 6h with a maximum percentage inhibition of 89.88% (6h) at the dose of 600mg/kg. ConclusionThese results demonstrate that the methanol extract of A. klaineanum may possess analgesic and anti-inflammatory effects and provide support of the traditional use of this plant in the treatment of different pain and inflammatory conditions. Further investigation could reveal metabolites of the extract responsible for the observed effects.

Pain catastrophizing may moderate the association between pain and secondary hyperalgesia.

Catastrophizing, a persistent negative mental set characterized by helplessness, rumination, and magnification of pain sensations, has a potent effect on pain report and clinical outcomes. Previous studies have documented an association between cognitive factors and central sensitization. The current analysis sought to test the potential modulating effect of pain catastrophizing on the association between capsaicin pain and the region of secondary hyperalgesia. Thirty-eight healthy individuals (50% women, mean age = 25.7, SD = 5.3) completed the Pain Catastrophizing Scale (PCS), then underwent topical application of 10% capsaicin, which was covered by a thermode maintained at 40°C for 90-min. Following removal of the capsaicin, the region of secondary hyperalgesia was determined. Hayes' PROCESS macro was employed to examine catastrophizing's potential moderating effect, which did not reveal a significant association between capsaicin pain ratings and the region of secondary hyperalgesia (β = 15.1, p = .06). Though PCS was not associated with area of secondary hyperalgesia (β = 23.9, p = .29), a significant interaction was present between PCS and capsaicin pain ratings (β = 3.7, p = .0004). Specifically, those endorsing higher catastrophizing levels and higher pain ratings experienced the greatest areas of secondary hyperalgesia. The Johnson-Neyman technique was used to determine the regional effect of the moderation, which indicated that when PCS scores were ≥10.6, capsaicin pain significantly moderated the association between pain and area of secondary hyperalgesia. These results suggest that catastrophizing plays an important role in the area of secondary hyperalgesia, and potentially central sensitization, warranting further testing in future research.

Ethnic Differences in the Effects of Naloxone on Sustained Evoked Pain: A Preliminary Study.

Ethnic differences in pain response have been well documented, with non-Hispanic Black (NHB) participants reporting enhanced clinical pain and greater laboratory-evoked pain sensitivity to a variety of quantitative sensory testing (QST) methods compared to non-Hispanic Whites (NHW). One potential mechanism that may contribute to these disparities is differential functioning of endogenous pain-regulatory systems. To evaluate endogenous opioid (EO) mechanisms in pain responses, we examined group differences in response to tonic capsaicin pain following double-blinded crossover administration of saline and the opioid antagonist, naloxone. Ten percent topical capsaicin cream and a thermode were applied to the dorsum of the non-dominant hand, maintaining a constant temperature of 40°C for 90 min. Naloxone (0.1 mg/kg) or saline placebo was administered at the 25 min mark and post-drug pain intensity ratings were obtained every 5 min thereafter. As an index of EO function, blockade effects were derived for each participant, reflecting the difference between mean post-drug pain intensity ratings under the saline versus naloxone conditions, with higher positive scores reflecting greater EO inhibition of pain. Thirty-nine healthy, young individuals (19 non-Hispanic Black [NHB], 20 non-Hispanic White [NHW]) participated. Group difference in EO function were identified, with NHB participants displaying lower EO function scores (mean=-10.8, SD=10.1) as compared to NHW participants (mean=-0.89, SD=11.5; p=0.038). NHB participants experienced significant paradoxical analgesia with naloxone. Thirty five percent of the NHW participants showed a positive blockade effect indicating EO analgesia (i.e., an increase in pain with naloxone), while only 10% of the NHB participants exhibited evidence of EO analgesia. These findings suggest differential functioning of the endogenous opioid pain regulatory system between NHB and NHW participants. Future research is warranted to examine whether these differences contribute to the disparities observed in clinical pain between groups.

Interaction of acupuncture treatment and manipulation laterality modulated by the default mode network.

Appropriate selection of ipsilateral or contralateral electroacupuncture (corresponding to the pain site) plays an important role in reaching its better curative effect; however, the involving brain mechanism still remains unclear. Compared with the heat pain model generally established in previous study, capsaicin pain model induces reversible cutaneous allodynia and is proved to be better simulating aspects of clinical nociceptive and neuropathic pain. In the current study, 24 subjects were randomly divided into two groups with a 2 × 2 factorial design: laterality (ipsi- or contralateral side, inter-subject) × treatment with counter-balanced at an interval of one week (verum and placebo electroacupuncture, within-subject). We observed subjective pain intensity and brain activations changes induced by capsaicin allodynia pain stimuli before and after electroacupuncture treatment at acupoint LI4 for 30 min. Analysis of variance results indicated that ipsilateral electroacupuncture treatment produced significant pain relief and wide brain signal suppressions in pain-related brain areas compared with contralateral electroacupuncture. We also found that verum electroacupuncture at either ipsi- or contralateral side to the pain site exhibited comparable significant magnitudes of analgesic effect. By contrast, placebo electroacupuncture elicited significant pain reductions only on the ipsilateral rather than contralateral side. It was inferred that placebo analgesia maybe attenuated on the region of the body (opposite to pain site) where attention was less focused, suggesting that analgesic effect of placebo electroacupuncture mainly rely on the motivation of its spatial-specific placebo responses via attention mechanism. This inference can be further supported by the evidence that the significant interaction effect of manipulation laterality and treatment was exclusively located within the default mode network, including the bilateral superior parietal lobule, inferior parietal lobule, precuneus, and left posterior cingulate cortex. It is also proved that disruptions of the default mode network may account for the cognitive and behavioral impairments in chronic pain patients. Our findings further suggested that default mode network participates in the modulation of spatial-oriented attention on placebo analgesia as a mechanism underlying the degree to which treatment side corresponding to the pain.

Distinct BOLD fMRI Responses of Capsaicin-Induced Thermal Sensation Reveal Pain-Related Brain Activation in Nonhuman Primates.

BackgroundApproximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored.MethodologyHere we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42°C; OFF:40 s/35°C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42°C or 48°C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail).Principal FindingsGroup comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the ‘pain matrix’, including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures.ConclusionsThese findings provide insights into the specific brain regions involved with aversive, ‘pain-like’, responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate the preclinical efficacy of novel analgesics.