Capsaicin-induced Pain Research Articles

The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure-Synthesis and In Vivo/In Vitro Studies.

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.

Design, synthesis and pharmacological profile of (−)-verbenone hydrazones

AbstractA series of novel (−)-verbenone hydrazones was designed and synthesized via condensation of terpenoid with hydrazides derived from phenoxyacetic acid. The structure of target compounds was confirmed by 1H-NMR and 13C-NMR analysis, Raman and FT-IR spectroscopy, electrospray ionization method and fast atom bombardment (FAB) mass spectrometry. Thermal properties of (−)-verbenone hydrazones 3a–3e were estimated by differential scanning calorimetry and their purity by HPLC coupled to mass spectrometry. Verbenone hydrazones were revealed to exist as Z/E geometrical isomers about C═N bond and cis/trans amide conformers. Verbenone derivatives were estimated as potential anticonvulsant agents after their oral administration against pentylenetetrazole and maximal electroshock-induced seizures in mice. Analgesic effect of hydrazones was studied by topical application on models of allyl isothiocyanate and capsaicin-induced pain. The present findings indicate that verbenone hydrazones contribute to seizure protection both at short (6 h) and long (24 h) time periods by blocking chemical- and electroshock-induced convulsions. Binding of compounds 3a–3e to TRPA1/TRPV1 ion channels was suggested as a feasible mechanism explaining their significant analgesic activity.

Capsaicin-induced pain sensitivity in short tear break-up time dry eye

PurposeTo evaluate transient receptor potential vanilloid 1 (TRPV1)-mediated pain sensitivity in patients with short tear break-up time (TBUT) dry eye (DE) by using the capsaicin stimulus test. MethodsThis prospective cross-sectional comparative study included 22 eyes of 22 patients with short TBUT DE and 11 eyes of 11 non-DE control subjects. Patients were divided into two groups based on response to standard DE treatments: 10 non-responders (intractable DE) and 12 responders (responsive DE). Mechanical touch (M-touch) and mechanical pain (M-pain) were measured using a Cochet-Bonnet esthesiometer. Capsaicin-induced pain (C-pain) and C-pain duration (C-pain DT) were measured using a capsaicin stimulus test. Psychological distress was also assessed. ResultsM-touch sensitivity was similar among all three groups. M-pain sensitivity was higher in the responsive DE group than in the intractable DE and control groups (P < .001). C-pain sensitivity was lower (P < .001) in the intractable DE group than in the responsive DE and control groups, and C-pain DT was shorter (P = .006) in the intractable DE group than in the responsive DE group. Psychological distress was higher in the intractable DE group than in the control group (P < .001). ConclusionsPatients with intractable short TBUT DE were less sensitive to the effects of capsaicin than patients with responsive short TBUT DE and controls. Altered neural activation may contribute to the development of DE symptoms in the short TBUT DE subjects. The capsaicin stimulus test may be used to better understand pain sensitivity in short TBUT DE patients.

Anti-oedematous and antinociceptive activities assessment of stem bark aqueous extract of Ficus exasperata Vahl. (Moraceae) in rat and mice.

Abstract Background: Ficus exasperata Vahl. (Moraceae) is widely used in African traditional medicine for the treatment of various diseases. The present study is undertaken to assess the anti-oedematous and antinociceptive activities of the stem bark aqueous extract of Ficus exasperata in mice and rats. Methods: The anti-oedematous activity was investigated following carrageenan or histamine-induced rat paw oedema models. Antinociceptive activity was evaluated using acetic acid induced writhing test (1 %, 10 ml/kg), capsaicin-induced neurogenic pain (32 µg/mL, 30 µL) and formalin-induced test (1%, 20 µL). Extract was administrated orally at 37.5, 75 and 150 mg/kg. Results: Pre-treatment of rats with Ficus exasperata stem bark aqueous extract exhibited significant inhibition of paw oedema during all the phases of both carrageenan and histamine induced edema in rat. The maximum inhibition percentages were 94.75 % (3 h) and 30.64 % after one hour at the dose of 37.5 mg/kg, respectively, in carrageenan or histamine models. Antinociceptive activity showed that aqueous extract reduced significantly (p &lt; 0.001) the pain induced by acetic acid with an inhibition percentage of 70.8% (150 mg/kg). In the formalin-induced test, the extract also reduced significantly (p &lt; 0.001) licking time during neurogenic phase and inflammatory phase with inhibition percentages of 44.75% and 52.78% respectively at the dose of 75 and 150 mg/kg. In addition, aqueous extract of F. exasperata reduced significantly (p &lt; 0.001) neurogenic pain induced by capsaïcin by 71.28 % at the highest dose (150 mg/kg). Conclusion: This finding suggests that the stem bark aqueous extract of Ficus exasperata possess potent anti-oedematous and antinociceptive activities. Keywords: Aqueous extract; anti-oedematous; antinociceptive; Ficus exasperata.

Pharmacological evaluation of analgesic, anti-inflammatory and antipyretic activities of ethanolic extract of Indigofera argentea Burm. f.

Ethnopharmacological relevanceIndigofera argentea Burm. f.; commonly known as neel, jantari, hathio; is traditionally used for the treatment of headache, fever, inflammation and body pain. Local communities also used this plant for the treatment of malaria, jaundice, vertigo and gastric disorders. Aim of the studyThis study is aimed to evaluate the toxicity and possible analgesic, anti-inflammatory and antipyretic activities of the ethanolic crude extract of Indigofera argentea (IaCr) to support its use in folk medicine and to screen the phytochemical constituents and antioxidant activity. Materials and methodsAqueous ethanolic (30:70) extract of whole plant of Indigofera argentea (IaCr) was prepared and phytochemical study was performed by preliminary methods followed by HPLC and DPPH method. In vivo experiments were performed in Wistar albino rats including hot plate, tail immersion, formalin and capsaicin-induced pain tests in rats and acetic acid-induced writhing test in mice. Anti-inflammatory activity was assessed by using in vitro human red blood cell (HRBC) membrane stabilization and carrageenan-induced rat paw edema test, while antipyretic activity was evaluated by Brewer’s yeast-induced pyrexia test. ResultsThe crude extract of Indigofera argentea confirmed the presence of flavonoids, glycosides, alkaloids, saponins and tannins as soluble ethanolic constituents in preliminary study. The maximum quantity of gallic acid equivalent (GAE) phenolics, and quercetin equivalent (QE) flavonoid content found was 81 ± 2 mg GAE/g and 56 ± 1.4 mg QE/g of extract respectively. Quantification based on HPLC exposed the presence of phenols and flavonoids, quercetin, gallic acid, caffeic acid, chlorogenic acid, benzoic acid, ferulic acid and coumaric acid. In vivo experiments revealed significant P < 0.05) dose-dependent inhibition in hot plate, tail immersion and capsaicin-induced pain test. IaCr showed significant inhibition of pain latency against both phases in formalin test and considerably decreased the number of writhes caused by acetic acid at the doses of 30, 100 and 300 mg/kg. In the in vitro anti-inflammatory (HRBC) assay, IaCr showed good membrane stability with maximum percentage hemolysis inhibition of 49.29% while in carrageenan-induced paw edema test in rats the IaCr showed significant anti-inflammatory action in a dose-dependent fashion. Statistical significant reduction in rectal temperature was observed at the doses of 100 and 300 mg/kg in yeast-induced pyrexia test in rats. ConclusionThe results of the experimental studies proved the analgesic, anti-inflammatory and antipyretic activities of Indigofera argentea and supported the traditional use of this plant.

Capsaicin-induced Pain and Sensation in the Postpartum Period

(Br J Anaesth. 2019;122(1):103–110) As observed in previous studies, a more rapid recovery from pain in the postoperative weeks following a cesarean delivery occurs than in other standard surgical procedures. Peripheral and central oxytocin release increases at the time of delivery and persists throughout lactation. A role for oxytocin in modulating pain neurotransmission is suggested by the recovery of animals from hypersensitivity after surgery in the postpartum period by the injection of intrathecal antagonists of oxytocin action. The primary goal of this study was to determine whether endogenous pain sensitization or inhibition was altered in postpartum women compared with an age-matched control group.

Pack-years of tobacco cigarette smoking as a predictor of spontaneous pain reporting and experimental pain reactivity.

The pack-years formula is a widely used estimate of lifetime tobacco smoking exposure, and greater pack-years have been associated with greater risk of chronic pain development and poorer pain-related outcomes among smokers with chronic pain. The pathophysiology underlying these associations is poorly understood. Regular tobacco smoking exposure may dysregulate homeostatic pain processes, producing an allostatic state of pain facilitation. Maladaptive pain mechanisms, such as central and peripheral sensitization, are chronic pain risk factors. Yet no published research has examined the relation between lifetime-smoking exposure and dysregulated pain processing. The current study used hierarchical linear regression analyses to test pack-years of tobacco smoking as a predictor of (a) pain reporting (current pain severity, pain frequency in the last 180 days) among a sample of 228 daily smokers without chronic pain, and (b) experimental capsaicin-induced pain reactivity (pain intensity, area of flare, mechanical pain sensitivity, and area of mechanical hyperalgesia) among 101 daily smokers without chronic pain. As hypothesized, results indicated that pack-years smoking was positively and significantly associated with current pain severity, past 180-day pain frequency, experimental pain intensity, mechanical pain sensitivity ratings, and area of mechanical hyperalgesia. Pack-years smoking was not significantly associated with neurogenic flare. These findings implicate central sensitization as a factor that may underlie the association between chronic tobacco smoking and increased risk for persistent pain. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Effects of High Definition Transcranial Direct Current Stimulation Targeting the Primary Motor Cortex on Experimental Capsaicin-Induced Pain in Healthy Volunteers

AbstractBackground: Chronic pain is one of the most common health problems in the world and a significant challenge to clinical practice. Which has severe effects on patient's social and daily work that costs a lot of the governmental support. Traditionally, the focus on alleviating chronic pain has relied mainly on pharmacotherapy which has limited efficacy and significant side-effects, especially with of prolonged use. Especially with opioids which is the most widely prescribed drugs for pain.Transcranial Direct Current Stimulation (tDCS) which deliver a weak current up to (2mA) through electrodes on the scalp has attracted much interest as it is safe, inexpensive and easy to implement and can be used as an alternative or adjuvant to pharmacotherapy.Aim of Study: In this study, we aimed to test the effects of the newly developed and more focally targeted anodal High Definition transcranial Direct Current Stimulation (HD-tCDS) targeting the PMC on a capsaicin-induced pain model in healthy subjects. We set out to test the hypothesis that it is possible to use HD-tDCS to stimulate the PMC and to compare this with sham stimulation.Patients and Methods: After obtaining informed consent, 36 healthy volunteers (20 male). All volunteers subjected to the following experimental paradigm: Application of capsaicin cream (0.075%) on a 9cm2 area of skin for 30 minutes on the volar surface of both forearms. The volunteers were blinded and then divided into two groups of 18 with each subjected to 20 minutes of the following: Group 1 received Sham HD tDCS targeting PMC, group 2 anodal HD tDCS (2mA) targets the PMC. Pain severity was collected using Numerical Rating Scale (NRS) score at regular intervals before and after the session. The subjects also asked whether they were able to differentiate between sham and active stimulation and any complications of stimulation recorded. The NRS scores also compared between the two groups. Statistical significance was calculated using suitable tests and pResults: Compared to sham stimulation, the PMC stimu-lation by HD-tDCS associated with a faster reduction in NRS pain scores after application of capsaicin to forearm skin. Also, it was well tolerated without documented adverse effect that necessitates discontinuation of the session.Conclusion: Anodal HD-tDCS of the primary motor cortex was associated with a faster reduction in reported pain score when compared with sham stimulation. Which can be used as a new treatment option for different chronic pain conditions.

Prostaglandin D2-glycerol ester decreases carrageenan-induced inflammation and hyperalgesia in mice

Pain is one of the cardinal signs of inflammation and is present in many inflammatory conditions. Therefore, anti-inflammatory drugs such as NSAIDs also have analgesic properties. We previously showed that prostaglandin D2-glycerol ester (PGD2-G), endogenously produced by cyclooxygenase-2 from the endocannabinoid 2-arachidonoylglycerol, has anti-inflammatory effects in vitro and in vivo that are partly mediated by DP1 receptor activation. In this work, we investigated its effect in a model of carrageenan-induced inflammatory pain. PGD2-G decreased hyperalgesia and edema, leading to a faster recovery. Moreover, PGD2-G decreased carrageenan-induced inflammatory markers in the paw as well as inflammatory cell recruitment. The effects of PGD2-G were independent from metabolite formation (PGD2 and 15d-PGJ2-G) or DP1 receptor activation in this model. Indeed PGD2 delayed recovery from hyperalgesia while 15d-PGJ2-G worsened the edema. However, while PGD2-G decreased hyperalgesia in this model of inflammatory pain, it had no effect when tested in the capsaicin-induced pain model. While the targets mediating the effects of this bioactive lipid in inflammatory pain remain to be elucidated, our findings further support the interest of anti-inflammatory lipid mediators in the management of inflammatory pain.

Capsaicin-induced pain and sensitisation in the postpartum period

BackgroundRecovery from Caesarean delivery in women and surgical nerve injury in animals after delivery is more rapid than expected, an effect reversed in animals by spinal injection of an oxytocin receptor antagonist. We hypothesised that endogenous modulation of acute pain is altered postpartum. MethodsEndogenous inhibition of acute pain in a conditioned pain modulation paradigm or endogenous sensitisation by topical capsaicin was tested in women who were breastfeeding 10–14 days after Caesarean delivery and age-matched controls (n=80 total: 20 per group and 20 per test). The study was powered to detect a difference in area of hyperalgesia after capsaicin of 33%. Capsaicin-evoked pain was recorded in women, and capsaicin-evoked mechanical hypersensitivity was measured in rats 48 h after delivery and in age-matched female and male animals. ResultsThere was no effect of the postpartum period in the endogenous sensitisation assay in women, and the conditioned pain modulation assay failed to produce analgesia in either group. Postpartum women, however, reported less intense pain than controls at the end of topical capsaicin exposure (1.3 [1.4] vs 2.0 [2.0] on 0–10 verbal scale), and acute hypersensitivity after capsaicin was less in postpartum than control rats (withdrawal threshold 25 [15] vs 3.6 [1] g). ConclusionsThese results agree with a recent report that oxytocin may desensitise the transient receptor potential for vanilloid-1 channel, although other explanations, including hormone effects, are possible. These results do not, however, support the inhibition of capsaicin-evoked spinal sensitisation in the postpartum period. Clinical trial registrationNCT01843517.

Neuron activity–induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit

Brain-derived neurotrophic factor (BDNF) is a master regulator of synaptic plasticity in various neural circuits of the mammalian central nervous system. Neuron activity-induced BDNF gene expression is regulated through the Ca2+/CREB pathway, but other regulatory factors may also be involved in controlling BDNF levels. We report here that Wnt/β-catenin signaling plays a key role in controlling neuron activity-regulated BDNF expression. Using primary cortical cultures, we show that blockade of Wnt/β-catenin signaling inhibits the BDNF up-regulation that is induced by activation of the N-methyl-d-aspartic acid (NMDA) receptor and that activation of the Wnt/β-catenin signaling pathway stimulates BDNF expression. In vivo, Wnt/β-catenin signaling activated BDNF expression and was required for peripheral pain-induced up-regulation of BDNF in the mouse spine. We also found that conditional deletion of one copy of either Wntless (Wls) or β-catenin by Nestin-Cre-mediated recombination is sufficient to inhibit the pain-induced up-regulation of BDNF. We further show that the Wnt/β-catenin/BDNF axis in the spinal neural circuit plays an important role in regulating capsaicin-induced pain. These results indicate that neuron activity-induced Wnt signaling stimulates BDNF expression in the pain neural circuits. We propose that pain-induced Wnt secretion may provide an additional mechanism for intercellular coordination of BDNF expression in the neural circuit.

The antiviral alkaloid berberine ameliorates neuropathic pain in rats with peripheral nerve injury.

Neuropathic pain is a major public health problem. There is a need to develop safer and more effective analgesia compounds with less side effects. Berberine has been used to treat diarrhea and gastroenteritis due to its anti-microbial, anti-motility and anti-secretory properties. Berberine has also been reported to play an analgesic role in some pathological conditions of pain. However, the analgesic roles of berberine in neuropathic pain are still unclear. Therefore, this study aims to explore the analgesic effects of berberine in neuropathic pain. Partial sciatic nerve ligation (pSNL) was performed to create neuropathic pain model. Paw withdrawal responses to mechanical and thermal stimuli were measured using a set of electronic von Frey apparatus and hot plate, respectively. The time that rats spent licking, flinching and lifting its paw during 5min following capsaicin application was recorded. mRNA and protein expression levels were examined by quantitative RT-PCR and western blot, respectively. Berberine administration (i.p.) increased both mechanical and thermal pain thresholds in a dose-dependent manner. Moreover, berberine administration reversed the mRNA and protein expression of TRPV1 in dorsal root ganglion neurons after peripheral nerve injury. In addition, berberine significantly inhibited capsaicin-induced pain behaviors. The amelioration of neuropathic pain by berberine may be associated with the down-regulation of TRPV1 in DRG of neuropathic pain rats. This study highlighted the potential of berberine in the treatment of neuropathic pain originated in the peripheral nervous system.

RAPID INDUCTION ANALGESIA FOR CAPSAICIN-INDUCED PAIN IN UNIVERSITY STUDENTS: A Randomized, Controlled Trial

The effect of rapid-induction analgesia (RIA) hypnosis on capsaicin-induced pain was tested in 60 healthy volunteers allocated randomly to 1 of 3 conditions: listening to an RIA recording several times before and then during the session, only the in-session RIA intervention, or listening to relaxing music (the control condition). Participants who had listened to the RIA recording beforehand were significantly more relaxed than controls when differences between the groups were identified for pain intensity. These findings suggest that relaxation induced by RIA recordings can alleviate the affective component of pain. In addition, benefits of RIA may strengthen with practice.

Nicotine deprivation increases pain intensity, neurogenic inflammation, and mechanical hyperalgesia among daily tobacco smokers.

An evolving reciprocal model posits that pain and tobacco smoking behavior interact in the manner of a positive feedback loop, resulting in greater pain and the maintenance of nicotine dependence. There is also reason to believe that abstaining from smoking may increase pain during the early stages of smoking cessation. The goal of this study was to test the effects of nicotine deprivation on experimental pain reactivity. Daily tobacco cigarette smokers (N = 165; 43% female) were randomized to either extended nicotine deprivation (12-24 hr smoking abstinence), minimal deprivation (2 hr smoking abstinence), or continued smoking conditions, prior to undergoing pain induction via topical capsaicin. As hypothesized, results indicated that extended deprivation (relative to continued smoking) increased capsaicin-induced pain intensity ratings, neurogenic inflammation, and mechanical hyperalgesia, thus implicating both central and peripheral mechanisms of action in the effects of smoking abstinence on pain reactivity. Pain intensity ratings were also positively correlated with nicotine withdrawal symptoms, and exploratory analyses suggest that pain sensitivity may increase with duration of smoking abstinence. Collectively, these findings indicate that smokers may experience a variety of negative pain-related sequelae during the early stages of a quit attempt. Future research should examine pain as a consequence or correlate of the nicotine withdrawal syndrome, and determine whether smokers may benefit from tailored cessation interventions that account for nicotine deprivation-induced amplification of pain. (PsycINFO Database Record

Chemical Composition and Antinociceptive Potential of Plinia edulis Fruits Peels

The present study deals with the chemical composition and antinociceptive effects of Plinia edulis fruit peels, analyzed by writhing, formalin, glutamate and capsaicin tests and comparison with two reference analgesic drugs, acetylsalicylic acid and acetaminophen. Phytochemical analyses of the nonpolar fraction (dichloromethane) obtained from the peels of P. edulis fruits revealed the presence of two triterpenes, maslinic acid and ursolic acid. The methanol extract of P. edulis peels showed a pronounced antinociceptive activity in the writhing test, with inhibition of 91.3% at 10 mg/kg, and its dichloromethane and ethyl acetate fractions presented inhibition of 68.3% and 51.5%, respectively. Maslinic acid showed a dose-dependent effect with inhibition of 60.8% at a dose of 10 mg/kg and ID50 value of 3.31 (2.75 to 4.0) mg/kg. The dichloromethane fraction, evaluated in the formalin-induced pain model at a dose of 10 mg/kg, showed a significant effect on both phases of pain. Maslinic acid was evaluated at different doses (1, 3 and 6 mg/kg) and presented a dose-dependent profile in both phases of pain, being more effective than the reference drug (acetaminophen), which was evaluated at 10 mg/kg. The dichloromethane fraction also inhibited the pain induced by glutamate and capsaicin by around 54% and 44%, respectively, whereas maslinic acid was more effective against glutamate, with 62.5% inhibition at 6 mg/kg, and 32% inhibition against capsaicin-induced pain. The results demonstrated that the pronounced antinociceptive effect presented by P. edulis fruits peels is related, at least in part, to the presence of the triterpenes evidenced in this study.

High Definition transcranial Direct Current (HD-tDCS) stimulation over the primary motor and insular cortex reduces capsaicin-induced pain and hyperalgesia: a placebo-controlled study

High Definition transcranial Direct Current (HD-tDCS) stimulation over the primary motor and insular cortex reduces capsaicin-induced pain and hyperalgesia: a placebo-controlled study

Clinical testing of three novel transient receptor potential cation channel subfamily V member 1 antagonists in a pharmacodynamic intradermal capsaicin model.

The transient receptor potential cation channel subfamily V 1 (TRPV1) is involved in nociception and has thus been of interest for drug developers, as a target for novel analgesics. However, several oral TRPV1 antagonists have failed in development, and novel approaches to target TRPV1 with innovative chemistry are needed. This work describes an intradermal microdosing approach in humans for pharmacodynamic deductions and pharmacological profiling of compounds. First, a human capsaicin model was developed, to generate pharmacodynamic translational data (Study Part A, n=24). Then, three small molecule TRPV1 antagonists (AZ11760788, AZ12048189 and AZ12099548) were investigated in healthy volunteers (Study Part B, n=36), applying the established model. Pain and flare were assessed by Visual Analogue Score and laser Doppler, respectively. The developed model proved useful for pharmacologic deductions; all compounds caused a dose-dependent inhibition of capsaicin-induced pain and flare responses, with a rank order potency of AZ11760788>AZ12048189≫AZ12099548. In addition, the dose-response data showed that the minimal antagonist concentrations needed to inhibit TRPV1 was ≥6-7 times the equilibrium dissociation constant for each compound. With careful design of a pharmacodynamic translational human pain model, it was possible to rank order TRPV1 efficacy among three investigational TRPV1 antagonists, and to estimate human efficacious concentrations. This fast and cost-effective translational approach allows for generation of human target engagement information early in drug development. This could be of value for other development programmes where pharmacological targets are expressed in peripheral sensory nerves.

Capsaicin 8% patch reversibly reduces A-delta fiber evoked potential amplitudes.

The capsaicin 8% patch is a treatment option in patients with localized peripheral neuropathic pain. Better understanding of its mechanisms of action and knowledge on predictive biomarkers for a treatment response is warranted. To use electrically evoked pain-related potentials for investigation of A-delta fiber conduction after capsaicin 8% patch treatment. We studied 11 healthy controls at the dorsal hand and the foot and 12 patients with neuropathic pain at the area affected by neuropathic pain before and 2 hours after application of a capsaicin 8% patch (Qutenza). Patients were additionally phenotyped using quantitative sensory testing and skin biopsy. Peak-to-peak N1-P1 amplitudes (PPA) were reduced after Qutenza application by a median of 60% in 6/11 controls and by 33% in patients with neuropathic pain compared with baseline; they were increased in 3 controls that did not develop capsaicin-induced pain. Patients with elevated cold detection thresholds more often had reduced PPA after Qutenza than those with normal cold detection threshold. Patients with reduced PPA after capsaicin application and with capsaicin-induced pain were more likely to achieve pain reduction on Qutenza. The capsaicin 8% patch induces a reduction in A-delta PPA in healthy persons and in patients with neuropathic pain adding to the mechanistic understanding of its effect.

Generalized Pain Sensitization and Endogenous Oxytocin in Individuals With Symptoms of Migraine: A Cross‐Sectional Study

The current study examined pain and neurogenic inflammation responses to topical capsaicin during the interictal period (between headache) and their relationship with plasma oxytocin in individuals with migraine. Individuals with migraine can experience generalized (extracephalic) hyperalgesia, which can persist even between headache attacks. Elevated levels of plasma and cerebrospinal fluid oxytocin have been observed during migraine attacks, oxytocin levels being positively associated with the intensity of migraine symptoms. However, whether oxytocin plays a role in the mechanisms of generalized pain sensitization and neurogenic inflammation during the interictal period has not been studied yet. Understanding migraineurs' interictal pain phenotype and endogenous oxytocin might help identify individuals who would benefit from intranasal oxytocin treatment. Thirty-two subjects with migraine and 26 healthy controls underwent pain testing. The current study compared capsaicin-induced pain, central sensitization (areas of secondary mechanical allodynia and hyperalgesia), and neurogenic inflammation (capsaicin-induced flare) responses on the nondominant volar forearm between migraineurs and healthy controls. Additionally, we studied plasma oxytocin levels and their relationship to migraine symptoms, experimental pain and affect. The results indicated a significant group effect (P = .019): Migraineurs reported greater capsaicin-induced pain unpleasantness (M = 1.2, SD = 1.4) on a 0-10 scale and showed larger areas of flare (LnM = 2.8, SD = 0.4) than healthy controls (M = 0.5, SD = 0.8; LnM = 2.6, SD = 0.4; ps < .032). In a subgroup analysis, enhanced capsaicin-induced pain unpleasantness was found in the chronic (P = .007), but not the episodic (Ps > .200), migraineurs. The oxytocin levels were elevated in migraineurs and accounted for 18% of the group difference in capsaicin-induced pain unpleasantness. Within migraineurs, interictal oxytocin levels were negatively associated with psychological distress (Ps < .030). However, during the interictal period, pain sensitivity in extracephalic regions and plasma oxytocin levels were unrelated to migraine symptom parameters (Ps > .074). Lastly, the results found no group difference in areas of secondary mechanical allodynia and hyperalgesia (Ps >.298). The current study revealed that individuals with migraine exhibit enhanced extracephalic capsaicin-induced pain unpleasantness and flare responses during interictal periods. In addition, migraineurs, especially those with chronic migraine, had slightly elevated interictal oxytocin levels compared to controls, which was associated with their affective component of experimental pain. Therefore, treatment targeting affective pain during the interictal period may help to reduce generalized pain in migraine. Furthermore, endogenous increases in oxytocin may be a compensatory mechanism that may help decrease affective distress in migraineurs. The therapeutic effects of intranasal oxytocin may benefit migraineurs by reducing their affective distress.

γ-Aminobutyric acid (GABA) oral rinse reduces capsaicin-induced burning mouth pain sensation: An experimental quantitative sensory testing study in healthy subjects.

In burning mouth patients, analgesia after oral administration of clonazepam may result from modulation of peripheral γ-aminobutyric acid (GABA) receptors. The effect of oral administration of test solutions (water, 0.5mol/L or 0.05mol/L GABA, 1% lidocaine) was investigated for the amelioration of pain and sensitivity induced by application of capsaicin (1%, 2min) to the tongue of thirty healthy male and female subjects in this four-session, randomized, placebo-controlled, double-blinded, cross-over study. Intra-oral quantitative sensory testing was used to assess cold (CDT), warm (WDT) and mechanical (MDT) detection thresholds as well as mechanical (MPT) and heat (HPT) pain thresholds. Capsaicin-induced pain intensity was continuously rated on a 0-10 electronic visual analogue scale (VAS). The area under the VAS curve (VASAUC) after rinsing was calculated for each solution. Capsaicin application on the tongue evoked burning pain with a peak of 4.8/10, and significantly increased CDT and MDT while significantly decreasing WDT, HPT, and MPT. The VASAUC was significantly smaller after oral rinse with 0.05mol/L GABA, 0.5mol/L GABA, and 1% lidocaine than after oral rinse with water. Rinse with 0.5mol/L or 0.05mol/L GABA were similarly effective in decreasing VASAUC. Rinsing with either 1% lidocaine, 0.5mol/L or 0.05mol/L GABA also significantly attenuated the effects of capsaicin on WDT and HPT in a treatment independent manner. There were no sex-related differences in these effects of GABA. Capsaicin-induced burning tongue pain and decreases in WDT and HPT can be ameliorated by rinsing the mouth with lidocaine and GABA solutions. Rinsing the mouth with an oral GABA containing solution ameliorated burning pain and increased heat sensitivity produced by application of capsaicin to the tongue. This finding suggests that GABA can act as a local analgesic agent in the oral cavity.