Different Models Of Pain Research Articles

Effectiveness of Botulinum Toxin for Oncologic Pain

Introduction: The use of botulinum toxin for medical purposes has expanded nowadays through the extensive study of its complex structure and mechanism of action, highlighting its ability to inhibit the release of acetylcholine, and its impact on the chemical signaling cascade involved in different models of pain.
 Objective: To evaluate the association of the use of botulinum toxin A with the reduction of pain in oncologic patients at Instituto Nacional de Cancerología, México.
 Methodology: A retrospective, observational, descriptive, and cross-sectional study was performed. Data were obtained from patients attended during the period from January 1, 2022 to September 30, 2023 in whom botulinum toxin was applied as an adjuvant for pain management.
 Results: Thirty-two patients who met the inclusion criteria were included. After the application of botulinum toxin there was a statistically significant reduction in pain, as measured by the Numeric Pain Rating Scale and Verbal Rating Scale. The degree of satisfaction after the application of botulinum toxin was measured by a Likert-type scale, and 68% satisfaction was found in the patients who underwent the onotoxin treatment.
 Conclusions: The use of botulinum toxin proved to be an effective and safe therapy, complementary to the multimodal approach for the treatment of different pain patterns in oncologic patients. It can be considered as a pharmacological option for use in this group of patients.
 Keywords: Oncologic pain, Pain management, Botulinum toxin

Assessing spontaneous sensory neuron activity using in vivo calcium imaging.

Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) through in vivo imaging in a mouse model of inflammatory pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used these data to train a machine learning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in 2 different models of pain: intraplantar complete Freund adjuvant and antigen-induced arthritis, with accuracies of 90.0% ±1.2 and 85.9% ±2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different laboratory using a different microscope configuration (accuracy = 94.0% ±2.2). We conclude that in vivo calcium imaging can be used to assess spontaneous activity in sensory neurons and provide a Google Colaboratory Notebook to allow anyone easy access to our novel analysis tool, for the assessment of spontaneous neuronal activity in their own imaging setups.

Potentiating TRPA1 by Sea Anemone Peptide Ms 9a-1 Reduces Pain and Inflammation in a Model of Osteoarthritis.

Progressive articular surface degradation during arthritis causes ongoing pain and hyperalgesia that lead to the development of functional disability. TRPA1 channel significantly contributes to the activation of sensory neurons that initiate neurogenic inflammation and mediates pain signal transduction to the central nervous system. Peptide Ms 9a-1 from the sea anemone Metridium senile is a positive allosteric modulator of TRPA1 and shows significant anti-inflammatory and analgesic activity in different models of pain. We used a model of monosodium iodoacetate (MIA)-induced osteoarthritis to evaluate the anti-inflammatory properties of Ms 9a-1 in comparison with APHC3 (a polypeptide modulator of TRPV1 channel) and non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam and ibuprofen. Administration of Ms 9a-1 (0.1 mg/kg, subcutaneously) significantly reversed joint swelling, disability, thermal and mechanical hypersensitivity, and grip strength impairment. The effect of Ms 9a-1 was equal to or better than that of reference drugs. Post-treatment histological analysis revealed that long-term administration of Ms9a-1 could reduce inflammatory changes in joints and prevent the progression of cartilage and bone destruction at the same level as meloxicam. Peptide Ms 9a-1 showed significant analgesic and anti-inflammatory effects in the model of MIA-induced OA, and therefore positive allosteric modulators could be considered for the alleviation of OA symptoms.

Age-dependent down-regulation of orexin receptors in trigeminal nucleus caudalis correlated with attenuation of orexinergic analgesia in rats

Aging is related to a variety of physiological organ changes, including central and peripheral nervous systems. It has been reported that the orexin signaling has a potential analgesic effect in different models of pain, especially inflammatory pulpal pain. However, the age-induced alteration in dental pain perception and orexin analgesia has not yet been fully elucidated.Here, we tested that how aging may change the effect of orexin-A on nociceptive behaviors in a rat dental pulp pain model. The expression levels of orexin receptors and the nociceptive neuropeptides substance P (SP) and calcitonin-related gene peptide (CGRP) were also assessed in the trigeminal nucleus caudalis (TNC) of young and aged rats. Dental pulp pain was induced by intradental application of capsaicin (100 μg). The immunofluorescence technique was used to evaluate the expression levels.The results show less efficiency of orexin-A to ameliorate pain perception in aged rats as compared to young rats. In addition, a significant decrease in the number of orexin 1 and 2 receptors was observed in the TNC of aged as compared to young rats. Dental pain-induced SP and CGRP overexpression was also significantly inhibited by orexin-A injection into the TNC of young animals. In contrast, orexin-A could not produce such effects in the aged animals.In conclusion, the older age-related reduction of the antinociceptive effect of orexin may be due to the downregulation of its receptors and inability of orexin signaling to inhibit the expression of nociceptive neuropeptides such as SP and CGRP in aged rats.

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy.

Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent. To begin to fill this knowledge gap, we assessed the anti-nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin-induced peripheral neuropathy, the formalin test, and the tail-flick assay. Using the von Frey test, we found that CBG-attenuated mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG-induced reduction in mechanical hypersensitivity was attenuated by the α2 -adrenergic receptor antagonist atipamezole (3mg/kg, i.p.) and the CB1 R antagonist, AM4113 (3mg/kg, i.p.), and blocked by the CB2 R antagonist/inverse agonist, SR144528 (10mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10mg/kg, i.p.) was more effective than pure CBG (10mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays. Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain. There are few effective treatments for neuropathic pain and neuropathic pain is projected to increase with the aging population. We demonstrate that CBG (cannabigerol) and CBG:CBD oil attenuate neuropathy-induced mechanical hypersensitivity mice. Second, we identify receptor targets that mediate CBG-induced reduction in mechanical hypersensitivity in neuropathic mice. Third, we demonstrate that an acute injection of CBG is anti-nociceptive specifically for neuropathic pain rather than other forms of pain, including persistent pain and thermal pain.

Pain modulates dopamine neurons via a spinal-parabrachial-mesencephalic circuit.

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior.

Non-Peptidergic Nociceptive Neurons Are Essential for Mechanical Inflammatory Hypersensitivity in Mice.

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

A review of objective assessments of orthopaedic analgesic efficacy of non-steroidal anti-inflammatory drugs in horses

There are a limited number of published objective assessments of the orthopaedic efficacy of various non-steroidal anti-inflammatory drugs (NSAIDs) in horses. Several different models of pain in horses have been used, but the least invasive orthopaedic model is the reversible foot lameness model using a shoe with either a mechanical heart bar or an eccentrically-placed threaded nut accommodating a bolt, with both models allowing variable levels of lameness after tightening of the bar or bolt against the solar surface of the foot. These and other models have yielded objective data, reviewed here, on NSAID efficacy in orthopaedic conditions. Phenylbutazone and flunixin are of comparable efficacy, and each is superior to ketoprofen, in the reversible model of foot pain, evidenced at rest, during treadmill exercise, and during recovery after exercise. The selective cyclooxygenase (COX)-2 inhibitor firocoxib, given either orally or intravenously, appears to be an effective alternative to traditional pan-COX-inhibiting NSAIDs, but an initial three-fold loading dose is necessary with intravenous firocoxib to achieve steady state and full efficacy faster than the label dose allows. Meloxicam has also been shown to be effective in two published orthopaedic studies. Acetaminophen/paracetamol has shown some initial promise in preliminary studies using the reversible model of foot pain. Combination therapy should involve appropriately-dosed NSAIDs with differing onsets and durations, whereas drugs with similar onsets and durations may not be synergistic. Sanctioning bodies and local or federal laws may restrict or prohibit the use of NSAIDs before or during equestrian competition.

Anti-nociceptive effect of stigmasterol in mouse models of acute and chronic pain.

Stigmasterol is a common sterol found in plants, but the anti-nociceptive effect of this compound and its mechanism of action are not fully explored. Thus, in the present study, the anti-nociceptive effect of stigmasterol was investigated in acute and chronic models of pain and its mechanism of action. We used adult male albino Swiss mice (25-35g) to observe the anti-nociceptive effect of stigmasterol in acetic-acid writhing test or in complete Freund's adjuvant injection, surgical incision in hind paw, or partial sciatic nerve ligation. Moreover, we investigate the involvement of opioid receptors (naloxone, 2mg/kg, intraperitoneally) in stigmasterol anti-nociceptive effect and stigmasterol action on acetylcholinesterase activity. Some possible adverse effects caused by stigmasterol were also investigated. Stigmasterol (0.3-3mg/kg, orally) exhibited an anti-nociceptive effect on acetic-acid-induced writhing test. Furthermore, it markedly attenuated the mechanical allodynia caused by surgical incision (after acute treatment with stigmasterol, preventive and curative effects were observed) and partial sciatic nerve ligation (after acute treatment with stigmasterol) and complete Freund's adjuvant (after acute or repeated treatment with stigmasterol). The anti-nociceptive effect of stigmasterol was not reversed by naloxone. Moreover, stigmasterol did not alter in vitro acetylcholinesterase activity in spinal cord or brain samples. Also, stigmasterol did not cause gastric ulcers or alter the gastrointestinal transit of mice. Taken together, these results support the potential anti-nociceptive effect of stigmasterol in different models of pain.

Experimental study of state of gastric mucosa in rats under introduction of new derivate of 4-[4-oxo-4h-quinazoline-3-yl] benzoic acid (PC-66)

Screening studies have revealed that the new derivate of 4-[4-oxo-4H-quinazoline-3-yl] benzoic acid (compound PC-66) possess significant antinociceptive and weakly expressed anti-inflammatory and antipyretic activity on different models of pain and inflammation. The cоndition of gastric defense under influence of PC-66 is unknown.The aim of this study was to explore the ability of PC-66 in comparison with diclophenac sodium produce gastric lesions on intact and rats with adjuvant arthritis, and to determine the role of influence on prostaglandin–H-synthase and stable metabolits of nitric oxide in the pathogenesis of these damages.Materials and methods: The impact of PC-66 compound and a diclofenac sodium was explored on macroscopic changes in gastric mucosa under conditions of long-term administration and of experimental inflammation.The spectrophotometric method revealed active prostaglandin-endoperoxide synthase in the rats` GM homogenates against accumulation of oxidized form of adrenaline electron donor. The total content of nitrites and nitrates was determined by reaction with Griess reagent after preliminary restoration of nitrates with a suspension of zinc dust in ammonia solution.Results and Discussion. PC-66 compound, unlike the reference medicine, did not cause significant gastric lesions under conditions of its long-term administration to intact rats. We found that during diclofenac administration, the activity of PGH-synthetase in GM significantly decreased compared to the control, whilst under the influence of PC-66, the activity of this enzyme remained practically unchanged. Administration of PC-66 compound to rats, unlike diclofenac, was associated with a significant increase of stable NO metabolites in GM, whilst this index decreased compared to control under the influence of investigational NSAID.Conclusions: 4- [4-oxo-4H-quinazoline-3-yl] benzoic acid has no damaging effect on the gastric mucosa both in intact animals and in rats with experimental inflammation. The basis of its GM safety rests on lacking inhibitory effect on production of vasodilator molecules in GM of PC-66 compound, unlike diclofenac sodium

Nicorandil inhibits neutrophil recruitment in carrageenan-induced experimental pleurisy in mice

Nicorandil is a drug characterized by the coupling of a nitric oxide (NO) donor to nicotinamide. We have previously demonstrated that nicotinamide exhibits activity in different models of pain and inflammation. Now, we investigated the effects induced by per os (p.o.) administration of nicorandil (25, 50 or 100mg/Kg) on neutrophil recruitment in a carrageenan-induced model of pleurisy in mice. Effects induced by nicorandil (100mg/kg) were compared with those induced by equimolar doses of nicotinamide (58mg/kg) and N-(2-hydroxyethyl)-nicotinamide (NHN; 79mg/kg). We also investigated whether effects on the production of inflammatory mediators play a role in the activity of nicorandil. P.o. nicorandil, 0.5h before and 1h after the i.pl. injection of carrageenan, reduced neutrophil recruitment. However, equimolar doses of nicotinamide or NHN failed to induce such effect. Single treatment (previous or late) with nicorandil (100mg/Kg, p.o.) also reduced neutrophils recruitment, although to a lesser extent when compared to the double treatment. Nicorandil reduced the concentrations of interleukin-1β, CXCL-1 and prostaglandin E2 in the pleural exudate. Concluding, we demonstrated the activity of nicorandil in a model of pleurisy induced by carrageenan. This activity was characterized by reduction of the neutrophil accumulation and inhibition of production of inflammatory mediators. The effects induced by nicorandil on the leukocytes recruitment and production of inflammatory mediators contribute to a better understanding of its clinical benefits and indicate that these benefits may be due to its vasodilating and anti-inflammatory activities.

Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer, in models of thermal, chemical and incisional pain in mice

Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, ω-conotoxin MVIIA and ω-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, ω-conotoxin MVIIC was effective only when post-administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not ω-conotoxin MVIIC, reversed NMDA-induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control.

Kaurenoic Acid from Sphagneticola trilobata Inhibits Inflammatory Pain: Effect on Cytokine Production and Activation of the NO–Cyclic GMP–Protein Kinase G–ATP-Sensitive Potassium Channel Signaling Pathway

Kaurenoic acid [ent-kaur-16-en-19-oic acid (1)] is a diterpene present in several plants including Sphagneticola trilobata. The only documented evidence for its antinociceptive effect is that it inhibits the writhing response induced by acetic acid in mice. Therefore, the analgesic effect of 1 in different models of pain and its mechanisms in mice were investigated further. Intraperitoneal and oral treatment with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid. Oral treatment with 1 also inhibited overt nociception-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), and both phases of the formalin test. Compound 1 also inhibited acute carrageenin- and PGE(2)-induced and chronic CFA-induced inflammatory mechanical hyperalgesia. Mechanistically, 1 inhibited the production of the hyperalgesic cytokines TNF-α and IL-1β. Furthermore, the analgesic effect of 1 was inhibited by l-NAME, ODQ, KT5823, and glybenclamide treatment, demonstrating that such activity also depends on activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that 1 exhibits an analgesic effect in a consistent manner and that its mechanisms involve the inhibition of cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway.

General pharmacology of the butanamide derivative S 19812, a new dual inhibitor of cyclooxygenase and lipoxygenase pathways.

S 19812 (N-hydroxy-N-methyl-4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl) butanamide, CAS 181308-68-9), a dual inhibitor of cyclooxygenase and lipoxygenase pathways, was evaluated in different models of pain and inflammation. Its gastric tolerance was also investigated. After acute oral treatment S 19812 exhibited a non-opioid analgesic activity observed in the phenylbenzoquinone-induced writhing model in mice (ED50 = 2.1 mg/kg) and in the carrageenan-induced hyperalgesia model in rats (ED50 = 9.1 mg/kg, preventive treatment; 8.3 mg/kg, curative treatment). Anti-inflammatory activity was observed in the adjuvant-induced arthritis in rat (inhibition of edema ED50 = 11 mg/kg/day p.o., day 28). In rats and mice, S 19812 exhibited an excellent gastric tolerance at doses up to 800 mg/kg p.o.

Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases

BackgroundMany studies have shown the antinociceptive effects of cannabinoid (CB) agonists in different models of pain. Herein, we have investigated their relevance in neuropathic pain induced by brachial plexus avulsion (BPA) in mice.Methodology/Principal FindingsMice underwent BPA or sham surgery. The mRNA levels and protein expression of CB1 and CB2 receptors were assessed by RT-PCR and immunohistochemistry, respectively. The activation of glial cells, MAP kinases and transcription factors were evaluated by immunohistochemistry. The antinociceptive properties induced by cannabinoid agonists were assessed on the 5th and 30th days after surgery. We observed a marked increase in CB1 and CB2 receptor mRNA and protein expression in the spinal cord and dorsal root ganglion, either at the 5th or 30th day after surgery. BPA also induced a marked activation of p38 and JNK MAP kinases (on the 30th day), glial cells, such as microglia and astrocytes, and the transcription factors CREB and NF-κB (at the 5th and 30th days) in the spinal cord. Systemic treatment with cannabinoid agonists reduced mechanical allodynia on both the 5th and 30th days after surgery, but the greatest results were observed by using central routes of administration, especially at the 30th day. Treatment with WIN 55,212-2 prevented the activation of both glial cells and MAP kinases, associated with an enhancement of CREB and NF-κB activation.Conclusions/SignificanceOur results indicate a relevant role for cannabinoid agonists in BPA, reinforcing their potential therapeutic relevance for the management of chronic pain states.

The antihyperalgesic effect of cytidine-5′-diphosphate-choline in neuropathic and inflammatory pain models

This study was designed to test the effects of intracerebroventricularly (i.c.v.) administered CDP-choline (cytidine-5'-diphosphate-choline; citicoline) and its metabolites in rat models of inflammatory and neuropathic pain. The i.c.v. administration of CDP-choline (0.5, 1.0 and 2.0 µmol) produced a dose and time-dependent reversal of mechanical hyperalgesia in both carrageenan-induced inflammatory and chronic constriction injury-induced neuropathic pain models in rats. The antihyperalgesic effect of CDP-choline was similar to that observed with an equimolar dose of choline (1 µmol). The CDP-choline-induced antihyperalgesic effect was prevented by central administration of the neuronal high-affinity choline uptake inhibitor hemicholinium-3 (1 µg), the nonselective nicotinic receptor antagonist mecamylamine (50 µg), the α7-selective nicotinic ACh receptor antagonist, α-bungarotoxin (2 µg) and the γ-aminobutyric acid B receptor antagonist CGP-35348 (20 µg). In contrast, i.c.v. pretreatment with the nonselective opioid receptor antagonist naloxone (10 µg) only prevented the CDP-choline-induced antihyperalgesic effect in the neuropathic pain model while the nonselective muscarinic receptor antagonist atropine (10 µg) did not alter the antihyperalgesic effect in the two models. These results indicate that CDP-choline-elicited antihyperalgesic effect in different models of pain occurs through mechanisms that seem to involve an interaction with supraspinal α7-selective nicotinic ACh receptors, and γ-aminobutyric acid B receptors, whereas central opioid receptors have a role only in the neuropathic pain model.

Screening of Ficus religiosa leaves fractions for analgesic and anti-inflammatory activities.

Objective:To evaluate the different fractions of dried leaves of Ficus religiosa Linn for analgesic and anti-inflammatory activity using different models of pain and inflammationMaterials and Methods:The analgesic activity of F. religiosa carried out using acetic acid-induced writhing in mice and tail flick test in rats. The anti-inflammatory activity was evaluated using carrageenan-induced rat paw edema and cotton pellet-granuloma formation in rats. Five different fractions (FRI, FRII, FRIII, FRIV and FRV) of F. religiosa at the dose level of 20 and 40 mg/kg, p.o were tested.Results:The fraction FRI (40 mg/kg, p.o.) and FRIII (40 mg/kg, p.o) were found to be more effective (P<0.01) in preventing carrageenan induced rat paw edema, cotton pellet granuloma formation, and acetic acid induced writhing compared to the other fractions. FRI (20 mg/kg, p.o.) and FRIII (20 mg/kg, p.o.) were also found to be more effective in increasing latency period in tail flick method.Conclusion:Out of five different fractions of F. religiosa leaves tested, FRI and FRIII possess potent analgesic and anti-inflammatory activities against different models of inflammation and pain.

MetaXCMS: second-order analysis of untargeted metabolomics data.

Mass spectrometry-based untargeted metabolomics often results in the observation of hundreds to thousands of features that are differentially regulated between sample classes. A major challenge in interpreting the data is distinguishing metabolites that are causally associated with the phenotype of interest from those that are unrelated but altered in downstream pathways as an effect. To facilitate this distinction, here we describe new software called metaXCMS for performing second-order ("meta") analysis of untargeted metabolomics data from multiple sample groups representing different models of the same phenotype. While the original version of XCMS was designed for the direct comparison of two sample groups, metaXCMS enables meta-analysis of an unlimited number of sample classes to facilitate prioritization of the data and increase the probability of identifying metabolites causally related to the phenotype of interest. metaXCMS is used to import XCMS results that are subsequently filtered, realigned, and ultimately compared to identify shared metabolites that are up- or down-regulated across all sample groups. We demonstrate the software's utility by identifying histamine as a metabolite that is commonly altered in three different models of pain. metaXCMS is freely available at http://metlin.scripps.edu/metaxcms/.

Evidence for the involvement of μ-opioid and δ-opioid receptors in the antinociceptive effect caused by oral administration of m-trifluoromethyl-diphenyl diselenide in mice

Pain is one of the most prevalent conditions, which limits productivity and diminishes quality of life. This study examined the antinociceptive effects of m-trifluoromethyl-diphenyl diselenide [(m-CF3-C6H4Se)2] on behavioral models of pain in mice. The involvement of opioid receptors in (m-CF3-C6H4Se)2-induced antinociception was evaluated in the tail-immersion test. (m-CF3-C6H4Se)2 exhibited significant inhibition of nociception induced by capsaicin (1.6 μg/paw, intraplantarly) (10-100 mg/kg, orally), and acetic acid (1.6%, 10 ml/kg, intraperitoneally) (1-100 mg/kg, orally), and in tail-immersion (50-100 mg/kg) and hot-plate (10-100 mg/kg) tests. The antinociception caused by (m-CF3-C6H4Se)2 in the tail-immersion test was significantly attenuated by naloxone (a nonselective opioid antagonist, 1 mg/kg, subcutaneously), naloxonazine (a selective μ-opioid receptor antagonist, 35 mg/kg, subcutaneously), or naltrindole (a selective δ-opioid receptor antagonist, 5 mg/kg, intraperitoneally). In contrast, (m-CF3-C6H4Se)2-induced antinociception was not affected by treatment with nor-binaltorphimine (a selective κ-opioid receptor antagonist, 10 mg/kg, subcutaneously) or naloxone methiodide (a peripherally restricted opioid antagonist, 1 mg/kg, subcutaneously). These results indicate that (m-CF3-C6H4Se)2-elicited antinociception in different models of pain through mechanisms that seem to involve an interaction with the central opioid system, more specifically μ-opioid and δ-opioid receptors.

Evaluation of antinociceptive effects of Galipea longiflora alkaloid extract and major alkaloid 2-phenylquinoline

The present study evaluated the antinociceptive properties of an alkaloid extract and 2-phenylquinoline obtained from the bark of Galipea longiflora Krause (Rutaceae) against different models of pain in mice. The results demonstrate that the alkaloid extract caused a pronounced antinociceptive effect with the main alkaloid detected, 2-phenylquinoline, exhibiting moderate activity. The alkaloid extract had a calculated ID50 value of 20.3 mg/kg i.p. and less than 50 mg/kg p.o. against the writhing test which proved to be more effective than the reference drugs when administered by both routes. The ID50 of 2-phenylquinoline was 52.8 mg/kg i.p. with an inhibition of 24.5% when administered orally at 100 mg/kg. In the formalin test the alkaloid extract, but not 2-phenylquinoline, significantly inhibited both phases of pain (neurogenic and inflammatory) at 10 mg/kg i.p. with inhibitions of 37.4% and 58.3%, respectively. The alkaloid extract and 2-phenylquinoline caused only a modest effect in the capsaicin and glutamate tests. In the hot plate test, the alkaloid extract increased the latency time by 25.6% at 10 mg/kg i.p. compared to 2-phenylquinoline which was less effective. It appears that the antinociceptive effects of this plant may be attributed, at least in part, to the presence of some antinociceptive alkaloids in minor concentrations.