Capsaicin-induced Pain Research Articles

Novel apocynin regulates TRPV1 activity in the trigeminal system and controls pain in a temporomandibular joint neurogenic model

ObjectiveHerein, we investigate the potential analgesic effect of a newly synthesized chalcone-derived apocynin in a neurogenic pain model. MethodsMolecular docking was used to foretell the apocynin binding features and dynamics with the TRPV1 channel, and the activity was tested in vitro, using transfected HEK 293T cells with the rat TRPV1 receptor. The analgesic effect of apocynin was investigated using a capsaicin-induced pain model. The expression of TRPV1, TRPA1, TRPM8, and MAPKs was assessed by electrophoresis, and immunosorbent assays were performed to quantify the neurotransmitters Substance P, Glutamate, and CGRP. A survival assay using Galleria mellonella was carried out to determine the toxicity. ResultsWe observed that apocynin exhibits greater thermodynamic stability. Upon apocynin ligand binding, it changes the electrostatic potential for a predominantly electronegative state in the interior and neutral in its external vanilloid pocket. Treatment of apocynin induces antinociceptive effects against the noxious challenge of capsaicin. Histologically, apocynin decreased the number of TRPV1+ immunopositive cells. Electrophoresis showed reduced phosphorylation of p44/42 (ERK1/2) and decreased protein levels of substance P, and CGRP. In the survival assay, apocynin showed low toxicity. ConclusionsIn conclusion, we provide proof-of-principles that the newly synthesized apocynin compound effectively prevented nociception in a neurogenic model of orofacial pain.

The Influence of Sex Steroid Hormone Fluctuations on Capsaicin-Induced Pain and TRPV1 Expression.

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain.

Novel Alaninamide Derivatives with Drug-like Potential for Development as Antiseizure and Antinociceptive Therapies─In Vitro and In Vivo Characterization.

In the present study, a series of original alaninamide derivatives have been designed applying a combinatorial chemistry approach, synthesized, and characterized in the in vivo and in vitro assays. The obtained molecules showed potent and broad-spectrum activity in basic seizure models, namely, the maximal electroshock (MES) test, the 6 Hz (32 mA) seizure model, and notably, the 6 Hz (44 mA) model of pharmacoresistant seizures. Most potent compounds 26 and 28 displayed the following pharmacological values: ED50 = 64.3 mg/kg (MES), ED50 = 15.6 mg/kg (6 Hz, 32 mA), ED50 = 29.9 mg/kg (6 Hz, 44 mA), and ED50 = 34.9 mg/kg (MES), ED50 = 12.1 mg/kg (6 Hz, 32 mA), ED50 = 29.5 mg/kg (6 Hz, 44 mA), respectively. Additionally, 26 and 28 were effective in the ivPTZ seizure threshold test and had no influence on the grip strength. Moreover, lead compound 28 was tested in the PTZ-induced kindling model, and then, its influence on glutamate and GABA levels in the hippocampus and cortex was evaluated by the high-performance liquid chromatography (HPLC) method. In addition, 28 revealed potent efficacy in formalin-induced tonic pain, capsaicin-induced pain, and oxaliplatin- and streptozotocin-induced peripheral neuropathy. Pharmacokinetic studies and in vitro ADME-Tox data proved favorable drug-like properties of 28. The patch-clamp recordings in rat cortical neurons showed that 28 at a concentration of 10 μM significantly inhibited fast sodium currents. Therefore, 28 seems to be an interesting candidate for future preclinical development in epilepsy and pain indications.

Evaluating The Analgesic Activity of Leaf, Stem Bark Extract And Isolated Nutraceuticals of <i>Caesalpinia Bonducella L (Roxb.)</i>

Evaluating The Analgesic Activity of Leaf, Stem Bark Extract And Isolated Nutraceuticals of <i>Caesalpinia Bonducella L (Roxb.)</i>

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Reduced capsaicin-induced mechanical allodynia and neuronal responses in the dorsal root ganglion in the presence of protein tyrosine phosphatase non-receptor type 6 overexpression.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region two domain-containing phosphatase-1 (SHP-1, encoded by Ptpn6) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Ptpn6 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Ptpn6 (Shp1-Tg) and their wild type (WT) littermates were used. Ptpn6 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Ptpn6 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Ptpn6 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.

Novel marine natural products as effective TRPV1 channel blockers

Chronic pain management poses a formidable challenge to healthcare, exacerbated by current analgesic options' limitations and adverse effects. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, has emerged as a promising target for novel analgesics. However, safety and tolerability concerns have constrained the development of TRPV1 modulators. In this study, we explored marine-derived natural products as a source of potential TRPV1 modulators using high-throughput dye-uptake assays. We identified chrexanthomycins, a family of hexacyclic xanthones, exhibited potent TRPV1 inhibitory effects, with compounds cC and cF demonstrating the most significant activity. High-resolution patch-clamp assays confirmed the direct action of these compounds on the TRPV1 channel. Furthermore, in vivo assays revealed that cC and cF effectively suppressed capsaicin-induced pain sensation in mice, comparable to the known TRPV1 inhibitor, capsazepine. Structural-activity relationship analysis highlighted the importance of specific functional groups in modulating TRPV1 activity. Our findings underscore the therapeutic potential of chrexanthomycins and pave the way for further investigations into marine-derived TRPV1 modulators for pain management.

Anti-nociceptive and Anti-inflammatory Activities of Visnagin in Different Nociceptive and Inflammatory Mice Models.

Pain management has been a severe public health issue throughout the world. Acute pain if not treated at the appropriate time can lead to chronic pain that can cause psychological and social distress. Nothing can be more rewarding than treating pain successfully for a physician. However, the use of chemical NSAIDs and opiate drugs has taken a toll on the patients with their unavoidable side effects. This study intends to explore the potential to treat pain by inhibiting nociception and inflammation with a safer, non-addictive, effective, and low-cost alternative agent from a natural source, visnagin. In vivo studies have been conducted using male Swiss albino mice as models for this research. Nociception was induced using different chemical and thermal stimuli such as acetic acid, glutamate, capsaicin, and formalin. To check for the anti-inflammatory properties, carrageenan was used to induce inflammation and the activity was assayed using peritoneal cavity leukocyte infiltration analysis and pro-inflammatory cytokine level comparison with the supplementation of visnagin at three different dosages. The findings of this study revealed that the visnagin treatment effectively attenuated the acetic acid-induced writhing response, glutamate-induced paw licking numbers, capsaicin-induced pain response, and formalin-induced biphasic licking incidences in the experimental mice models. Furthermore, the visnagin treatment remarkably suppressed the carrageenan-induced inflammation in mice, which is evident from the decreased leukocytes, mononuclear, and polymorphonuclear cell numbers in the mice. The levels of cytokines such as TNF-α, IL-1β, and IL-6 were effectively reduced by the visnagin treatment in the experimental mice. The results of open field test proved that the visnagin showed a better locomotor movement in the experimental mice. These results provided evidence for the potential activity of the visnagin against inflammatory and nociceptive responses in the mice.

Analyzing the Antinociceptive Effect of Interleukin-31 in Mice.

The theory that an itch inhibits pain has been refuted; however, previous research did not investigate this theory for an interleukin-31 (IL-31)-induced itch. Previously, we have found that morphine-induced antinociception was partially reduced in IL-31 receptor A (IL-31RA)-deficient (IL-31RAKI) mice, indicating that IL-31RA may play an important role in morphine-induced peripheral antinociception. In the present study, we evaluated the effect of IL-31-induced analgesia on a 2,4,6-trinitrochlorobenzene (TNCB)-sensitized mice using a hot-plate test. This test evaluated the antinociceptive activity of morphine and non-steroidal anti-inflammatory drugs (NSAIDs). Repeated pretreatment with IL-31 showed significant antinociceptive action. Furthermore, its combination with morphine, but not with NSAIDs, increased the analgesic action. In contrast, treatment with TNCB and capsaicin decreased antinociception. Moreover, TNCB increased IL-31RA expression in the dorsal root ganglia at 24 h, whereas capsaicin inhibited it. The comparative action of several analgesics on TNCB or capsaicin was evaluated using a hot-plate test, which revealed that the antinociceptive activity was decreased or disappeared in response to capsaicin-induced pain in IL-31RAKI mice. These results indicate that the analgesic action of IL-31 involves the peripheral nervous system, which affects sensory nerves. These results provide a basis for developing novel analgesics using this mechanism.

Decreased Default Mode Network Connectivity Following 24 Hours of Capsaicin-induced Pain Persists During Immediate Pain Relief and Facilitation

Prolonged experimental pain models can help assess cortical mechanisms underlying the transition from acute to chronic pain such as resting-state functional connectivity (rsFC), especially in early stages. This crossover study determined the effects of 24-hour-capsaicin-induced pain on the default mode network rsFC, a major network in the dynamic pain connectome. Electroencephalographic rsFC measured by Granger causality was acquired from 24 healthy volunteers (12 women) at baseline, 1hour, and 24hours following the application of a control or capsaicin patch on the right forearm. The control patch was received maximum 1 week before the capsaicin patch. Following 24hours, the patch was cooled and later heated to assess rsFC changes in response to pain relief and facilitation, respectively. Compared to baseline, decreased rsFC at alpha oscillations (8-10Hz) was found following 1hour and 24hours of capsaicin application for connections projecting from medial prefrontal cortex (mPFC) and right angular gyrus (rAG) but not left angular gyrus (lAG) or posterior cingulate cortex (PCC): mPFC-PCC (1hour:P < .001, 24hours:P = .002), mPFC-rAG (1hour:P < .001, 24hours:P = .001), rAG-mPFC (1hour:P < .001, 24hours:P = .001), rAG-PCC (1hour:P < .001, 24hours:P = .004). Comparable decreased rsFC following 1hour and 24hours (P≤0.008) was found at beta oscillations, however, decreased projections from PCC were also found: PCC-rAG (P≤0.005) and PCC-lAG (P≤0.006). Pain NRS scores following 24hours (3.7±0.4) was reduced by cooling (0.3±0.1, P = .004) and increased by heating (4.8±0.6, P = .016). However, neither cooling nor heating altered rsFC. This study shows that 24hours of experimental pain induces a robust decrease in DMN connectivity that persists during pain relief or facilitation suggesting a possible shift to attentional and emotional processing in persistent pain. PerspectiveThis article shows decreased DMN connectivity that might reflect possible attentional and emotional changes during acute and prolonged pain. Understanding these changes could potentially help clinicians in developing therapeutic methods that can better target these attentional and emotional processes before developing into more persistent states.

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.

Multifocal tDCS Targeting the Motor Network Modulates Event-Related Cortical Responses During Prolonged Pain

Multifocal transcranial direct current stimulation (tDCS) targeting several brain regions is promising for inducing cortical plasticity. It remains unknown whether multifocal tDCS aimed at the resting-state motor network (network-tDCS) can revert N2-P2 cortical responses otherwise attenuated during prolonged experimental pain. Thirty-eight healthy subjects participated in 2 sessions separated by 24 hours (Day1, Day2) of active (n = 19) or sham (n = 19) network-tDCS. Experimental pain induced by topical capsaicin was maintained for 24 hours and assessed using a numerical rating scale. Electrical detection and pain thresholds, and N2-P2 evoked potentials (electroencephalography) to noxious electrical stimulation were recorded before capsaicin-induced pain (Day1-baseline), after capsaicin application (Day1-post-cap), and after 2 sessions of network-tDCS (Day2). Capsaicin induced moderate pain at Day1-post-cap, which further increased at Day2 in both groups (P = .01). Electrical detection/pain thresholds did not change over time. N2-P2 responses were reduced on Day1-post-cap compared to Day1-baseline (P = .019). At Day2 compared with Day1-post-cap, N2-P2 responses were significantly higher in the Active network-tDCS group (P<.05), while the sham group remained inhibited. These results suggest that tDCS targeting regions associated with the motor network may modulate the late evoked brain responses to noxious peripheral stimulation otherwise initially inhibited by capsaicin-induced pain. PerspectiveThis study extends the evidence of N2-P2 reduction due to capsaicin-induced pain from 30 minutes to 24 hrs. Moreover, 2 sessions of tDCS targeting the motor network in the early stage of nociceptive pain may revert the inhibition of N2-P2 associated with capsaicin-induced pain.

Capsaicin-induced pain increases neural responses to low-calorie non-spicy food cues: An ERP study

Capsaicin, the main spicy ingredient in chili, can activate pain receptors on the human tongue and skin. Although some studies have determined that pain influenced preference for high-calorie foods, little is known whether pain can modulate the individuals’ preference for spicy foods and its neural mechanisms. After 30 participants underwent painful (topical capsaicin cream) and control (hand cream) treatments, an event-related potential (ERP) study was conducted to investigate the modulation of capsaicin-induced pain on food preference with food images. Results showed that both P3 and late positive potential (LPP) amplitudes during the painful treatment were significantly larger than those during the control treatment for low-calorie non-spicy food cues. However, for the other three categories of food cues, there were no significant differences between the two treatments. The present study suggests that capsaicin-induced pain increases individuals’ neural processing of low-calorie non-spicy food cues, which provides empirical evidence on the relationship between pain and neural responses to food cues to help optimize dietary interventions for patients experiencing pain.

Tacrolimus suppresses itch-related response in diet-induced atopic dermatitis model mice by reducing chloroquine-sensitive sensory neurons

Introduction: Itch (or pruritus) is a common symptom of atopic dermatitis (AD), which significantly decreases the patient’s quality of life. Tacrolimus ointment reduces pruritus in AD; however, the underlying mechanism is not fully understood. Methods: In the present study, we used a diet-induced AD mouse model to examine the antipruritic mechanism of tacrolimus. After induction of AD symptoms, the tacrolimus-containing ointment was applied once daily for 7 days. Responsiveness of isolated dorsal root ganglion (DRG) cells to various stimuli was examined by monitoring intracellular Ca2+ levels. Results: Repeated application of tacrolimus ointment attenuated spontaneous itch-related responses, even when skin barrier dysfunction, skin inflammation, and epidermal nerve sprouting were not ameliorated. Tacrolimus-treated mice also exhibited reduced scratching behavior induced by several pruritogens, such as histamine, SLIGRL-NH2, and chloroquine (CQ), although capsaicin-induced pain behavior was not affected. DRG cells from tacrolimus-treated mice showed significantly lower Ca2+ responses to CQ. Furthermore, a reduction in CQ-sensitive DRG neurons was observed after in vitro treatment with either tacrolimus or rapamycin. Discussion: CQ-sensitive (MrgprA3-expressing) DRG neurons are implicated as itch-specific sensory neurons. Therefore, topically applied tacrolimus may act directly on itch-signaling neurons, consequently suppressing various itch responses in AD mice.

Slick Potassium Channels Control Pain and Itch in Distinct Populations of Sensory and Spinal Neurons in Mice

Slick, a sodium-activated potassium channel, has been recently identified in somatosensory pathways, but its functional role is poorly understood. The authors of this study hypothesized that Slick is involved in processing sensations of pain and itch. Immunostaining, in situ hybridization, Western blot, and real-time quantitative reverse transcription polymerase chain reaction were used to investigate the expression of Slick in dorsal root ganglia and the spinal cord. Mice lacking Slick globally (Slick-/-) or conditionally in neurons of the spinal dorsal horn (Lbx1-Slick-/-) were assessed in behavioral models. The authors found Slick to be enriched in nociceptive Aδ-fibers and in populations of interneurons in the spinal dorsal horn. Slick-/- mice, but not Lbx1-Slick-/- mice, showed enhanced responses to noxious heat in the hot plate and tail-immersion tests. Both Slick-/- and Lbx1-Slick-/- mice demonstrated prolonged paw licking after capsaicin injection (mean ± SD, 45.6 ± 30.1 s [95% CI, 19.8 to 71.4]; and 13.1 ± 16.1 s [95% CI, 1.8 to 28.0]; P = 0.006 [Slick-/- {n = 8} and wild-type {n = 7}, respectively]), which was paralleled by increased phosphorylation of the neuronal activity marker extracellular signal-regulated kinase in the spinal cord. In the spinal dorsal horn, Slick is colocalized with somatostatin receptor 2 (SSTR2), and intrathecal preadministration of the SSTR2 antagonist CYN-154806 prevented increased capsaicin-induced licking in Slick-/- and Lbx1-Slick-/- mice. Moreover, scratching after intrathecal delivery of the somatostatin analog octreotide was considerably reduced in Slick-/- and Lbx1-Slick-/- mice (Slick-/- [n = 8]: 6.1 ± 6.7 bouts [95% CI, 0.6 to 11.7]; wild-type [n =8]: 47.4 ± 51.1 bouts [95% CI, 4.8 to 90.2]; P = 0.039). Slick expressed in a subset of sensory neurons modulates heat-induced pain, while Slick expressed in spinal cord interneurons inhibits capsaicin-induced pain but facilitates somatostatin-induced itch.

Photosensitive and Photoswitchable TRPA1 Agonists Optically Control Pain through Channel Desensitization.

Transient receptor potential ankyrin 1 (TRPA1) channel, as a nonselective ligand-gated cation channel robustly in dorsal root ganglion sensory neurons, is implicated in sensing noxious stimuli and nociceptive signaling. However, small-molecule tools targeting TRPA1 lack temporal and spatial resolution, limiting their use for validation of TRPA1 as a therapeutic target for pain. In our previous work, we found that 4,4'-(diazene-1,2-diyl)dianiline (AB1) is a photoswitchable TRPA1 agonist, but the poor water solubility and activity hinder its further development. Here, we report a series of specific and potent azobenzene-derived photoswitchable TRPA1 agonists (series 1 and 2) that enable optical control of the TRPA1 channel. Two representative compounds 1g and 2c can alleviate capsaicin-induced pain in the cheek model of mice through channel desensitization but not in TRPA1 knockout mice. Taken together, our findings demonstrate that photoswitchable TRPA1 agonists can be used as pharmacological tools for study of pain signaling.

Effect of Pregabalin on the Median Effective Plasma Concentration of Intravenous Alfentanil in Capsaicin-Induced Pain.

To apply the sequential up-down method to a human experimental pain model in order to examine the opioid-sparing effect of oral pregabalin on intravenous alfentanil. Double-blind, randomized, crossover. Academic university medical center. Thirty-one healthy males. The median effective plasma concentration of intravenous alfentanil was determined under two conditions: alfentanil alone (phase I) and alfentanil+ pregabalin (300 mg orally) (phase II). The alfentanil plasma level (after a computer-controlled infusion) producing a success criterion (at least 30% intradermal capsaicin-induced pain reduction compared with placebo) was used to determine higher or lower doses for each sequential subject. The median dose producing a success criterion and its confidence interval were determined. On the basis of the t test for a difference across phase and regression coefficients across groups, there was no opioid-sparing effect of pregabalin on alfentanil. Four subjects in phase I and five subjects in phase II did not complete the study. Two in phase I were technical failures, with the rest in both phases stopped because of side effects. Of the subjects who completed the study, six of 19 subjects in phase I and 11 of 12 subjects in phase II reported side effects. When the intradermal capsaicin-induced pain model was used in healthy volunteers, oral pregabalin had no opioid-sparing effects on intravenous alfentanil. This experimental model may be useful in studying analgesic interactions.

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

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.

Effect of Experimental Gestational Diabetes Mellitus on Mechanical Sensitivity, Capsaicin-Induced Pain Behaviors and Hind Paw Glabrous Skin Innervation of Male and Female Mouse Offspring.

PurposeGestational diabetes mellitus (GDM) induces cardiovascular and metabolic disturbances in offspring. However, the effects of GDM in pain processing in offspring and whether male and female offspring are equally affected is not well known. Thus, we determined: i) whether GDM in mice affects offspring hindpaw mechanical sensitivity, capsaicin-induced spontaneous pain-like behaviors, and epidermal nerve fiber density (ENFD); and ii) whether there is sexual dimorphism in these parameters in offspring from GDM dams.MethodsGDM was induced in pregnant ICR mice via i.p. streptozotocin (STZ). Then, glucose levels from dams and offspring were determined. Male and female offspring 2–3 months of age were evaluated for: a) baseline mechanical sensitivity of the hind paw by using von Frey filaments; b) number of flinches and time spent guarding induced by intraplantar capsaicin (0.1%); and c) density of PGP-9.5 and CGRP axons in the epidermis from the hind paw glabrous skin.ResultsPrepartum levels of glucose in STZ-treated dams were significantly increased compared to vehicle-treated dams; however, GDM or vehicle offspring displayed normal and similar blood glucose levels. Male and female GDM offspring showed significantly greater mechanical sensitivity and capsaicin-induced pain behaviors compared to vehicle offspring. Male GDM offspring displayed a slightly more intense nociceptive phenotype in the capsaicin test. PGP-9.5 and CGRP ENFD in hind paw glabrous skin were greater in male and female GDM offspring versus their controls. Sexual dimorphism was generally not observed in GDM offspring in most of the studied parameters.ConclusionThese results suggest GDM induced greater pain-like behaviors in adult offspring regardless of sex along with an increased ENFD of PGP-9.5 and CGRP in the hind paw glabrous skin. We show that GDM peripheral neuropathy differs from diabetic peripheral neuropathy acquired in adulthood and set the foundation to further study this in human babies exposed to GDM.

Effect of Topical Analgesia on Desensitization Following 8% Topical Capsaicin Application

To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, 2 skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in 1 placebo and 1 EMLA pretreated area, obtaining the following four areas: Capsaicin + EMLA, Capsaicin + Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-hour application of capsaicin. Warmth detection, heat pain sensitivity, and microvascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare.Overall, EMLA caused significant reductions in capsaicin-induced pain compared with placebo (P= .007) and enhanced the capsaicin-induced increase in superficial blood perfusion immediately after the 3-hour capsaicin application (P< .01). Regardless of pretreatment, capsaicin induced heat hyperalgesia immediately after the application (P< .001). Twenty-four hours post application, heat pain sensitivity was normalized. However, WDT increased significantly (P< .001). Capsaicin tended to reduce the itch intensity and significantly reduced the neurogenic flare (P< .05) induced by histamine compared with EMLA alone. The findings suggest that pretreatment with topical analgesic cream reduces application site pain without interfering with the 8% topical capsaicin-induced desensitization. PerspectivePretreatment with local anesthetic EMLA cream might be considered a good therapeutic option to reduce the pain associated with 8% capsaicin application currently used for treatment of neuropathic pain syndromes. This study also suggests the existence of a synergistic effect of capsaicin and EMLA on the process of neurogenic inflammation.