Central Antinociceptive Activity Research Articles

The possible mechanisms of protocatechuic acid-induced central analgesia

It is aimed to investigate the central antinociceptive effect of protocatechuic acid and the involvement of stimulation of opioidergic, serotonin 5-HT2A/2C, α2-adrenergic and muscarinic receptors in protocatechuic acid-induced central analgesia in mice. Time-dependent antinociceptive effects of protocatechuic acid at the oral doses of 75, 150 and 300 mg/kg were tested in hot-plate (integrated supraspinal response) and tail-immersion (spinal reflex) tests in mice. To investigate the mechanisms of action; the mice administered 300 mg/kg protocatechuic acid (p.o.) were pre-treated with non-specific opioid antagonist naloxone (5 mg/kg, i.p.), serotonin 5-HT2A/2C receptor antagonist ketanserin (1 mg/kg, i.p.), α2-adrenoceptor antagonist yohimbine (1 mg/kg, i.p.) and non-specific muscarinic antagonist atropine (5 mg/kg, i.p.), respectively. The antinociceptive effect of protocatechuic acid was observed at the doses of 75, 150 and 300 mg/kg in tail-immersion test, at the doses of 150 and 300 mg/kg in hot-plate test at different time interval. The enhancement in the latency of protocatechuic acid-induced response to thermal stimuli was antagonized by yohimbine, naloxone and atropine in tail-immersion test, while it was antagonized only by yohimbine and naloxone pretreatments in hot-plate test. These results indicated that protocatechuic acid has the central antinociceptive action that is probably organized by spinal mediated cholinergic and opiodiergic, also spinal and supraspinal mediated noradrenergic modulation. However, further studies are required to understand how protocatechuic acid organizes the interactions of these modulatory systems. As a whole, these findings reinforce that protocatechuic acid is a potential agent that might be used for pain relief. Additionally, the clarification of the effect and mechanisms of action of protocatechuic acid will contribute to new therapeutic approaches and provide guidance for new drug development studies.

Optimized extraction of pectin-like polysaccharide from Suaeda fruticosa leaves: Characterization, antioxidant, anti-inflammatory and analgesic activities

Box-Behnken design (BBD) was performed via ultrasound-assisted system to optimize extraction yield and total antioxidant ability of polysaccharides from Suaeda fruticosa. Three independent variables were studied: temperature, time and pH with optimal settings 90 °C, 37 min and 2.9, respectively. Under these settings, isolation yield and total antioxidant activity were 34.0% and 31.8 mg ascorbic acid equivalent/g material, respectively. Furthermore, preliminary structure study was carried out using UV–vis analysis, Fourier transform infrared spectroscopy (FT-IR) and Nuclear magnetic resonance (1D (1H, 13C NMR) and 2D (1H, 1H COSY, 1H/13C HSQC)) methods Size exclusion chromatography (SEC) determination revealed that polysaccharide extracted had an average molecular weight of 240 kDa. Chemical composition analyses showed that extracted polysaccharide was a pectin-like polysaccharide with uronic acid content (47.5%) and neutral monosaccharides (52.5%) constituted mainly of arabinose, mannose, galactose, rhamnose, glucose and xylose in the molar percentage of 48.63%, 5.85%, 29.42%, 7.96%, 6.54% and 1.60%, respectively. This sugar composition was typical of that of a galactoarabinan. Importantly, the optimum polysaccharide possesses significant potentials in antioxidant activity effect. Moreover, pharmacological investigation of extracted polysaccharide revealed a good anti-inflammatory effect and interesting peripheral as well as central antinociceptive activities.

The flavonoid 6-methoxyflavone allays cisplatin-induced neuropathic allodynia and hypoalgesia

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side-effect of several commonly used chemotherapeutic agents (such as cisplatin) that profoundly impairs patient quality of life. Unfortunately, neither prophylactic strategies nor symptomatic treatments have proven useful in this condition. Flavonoids are found ubiquitously in fruits and vegetables and exert a multiplicity of beneficial effects. In this study, the antinociceptive activity of 6-methoxyflavone (6-MF) was investigated and evaluated in comparison with gabapentin in a rat model of CIPN. The effect on motor balance was also assessed using the rotarod and footprint analysis paradigms. 6-MF possessed both peripheral and central antinociceptive activities against tonic and phasic nociceptive stimuli. Cisplatin administration (3.0mg/kg/week, i.p.) for four consecutive weeks generated temporal mechanical allodynia (decreased paw withdrawal threshold; PWT) and thermal hypoalgesia (increased paw thermal threshold; PTT) in the bilateral hindpaws. Daily treatment with 6-MF (25, 50 and 75mg/kg/day, i.p) for four weeks attenuated the cisplatin-induced expression of nocifensive behaviors observed as a significant increase in PWT and alleviation of PTT during the third and fourth weeks of cisplatin administration. Accordingly, daily gabapentin (75mg/kg, i.p) suppressed the expression of CIPN by normalizing the PWT and hotplate response latency. However, these antinociceptive actions were associated with motor impairment exemplified by a significant decrease in rotarod endurance latency and a deficit in the uniformity of step alternation. In contrast, 6-MF was devoid of these adverse side-effects. These findings suggested that 6-MF afforded desirable neuropathic pain alleviating effects in CIPN and it was devoid of gabapentin-like unwanted motor side-effects.

Evaluation of antinociceptive, antihyperglycemic, and membrane stabilizing activities of Garcinia lancifolia Roxb

This study was undertaken to examine the antinociceptive, antihyperglycemic, and membrane stabilizing activity with phytochemical screening of methanolic extract of Garcinia lanceifolia whole plant. The extracts were subjected to in-vivo antinociceptive, antihyperglycemic activity in laboratory animals and in-vitro membrane stabilizing activity. In peripheral antinociceptive activity, G. lanceifolia (400 and 200 mg/kg) exhibited significant (P < 0.001) inhibition of writhing with 59.15% and 49.30% respectively comparable to standard Diclofenac (54.92% inhibition). In central antinociceptive activity, the extract (400 and 200 mg/kg) exhibited significant analgesic activity having 78.31% (P < 0.05) and 89.95% (P < 0.01) elongation of reaction time respectively in 90 min after administration of sample comparable to the standard Morphine (708.99% elongation). In hypoglycemic activity, the extract (400 and 200 mg/kg) exhibit statistically significant (P < 0.001) antihyperglycemic activity compared to standard drug Glibenclamide (10 mg/kg) at different time interval. In membrane stabilizing activity assay, clearly evident that the methanolic extracts of G. lanceifolia were highly effective to prevent the lyses of erythrocytes induced by heat. The outcomes of the present study revealed that this plant possess noteworthy pharmacological activities that may be basis for further research to disclose feasible mode of action of the plant part.

Antinociceptive Activity of Methanolic Leaf Extract of Parthenium hysterophorus L.

The present study was aimed to evaluate the antinociceptive property of Parthenium hysterophorus L. The central antinociceptive activity was analyzed by hot plate and tail immersion method; whereas acetic acid-induced writhing test and formalin induced licking tests were carried out for peripheral antinociceptive activity. The acute toxicity study revealed that methanol extract of the plant was moderately toxic at a dose of 500 mg/kg body weight. In hot plate method and tail immersion test the methanol extract exhibited significant analgesic activity ( 𝑃 < 0.001) at a dose of 2.5 and 5 mg/kg revealed its central antinociceptive activity. The significant activity (p<0.01) in acetic acid induced writhing test and formalin induced licking test implies the peripheral antinociceptive property of the extract at both doses. These findings justify that P. hysterophorus L. can be a valuable natural antinociceptive source which seemed to provide potential phytotherapeutics against various ailments.

Antinociceptive effect of methanol extract of Dalbergia sissoo leaves in mice

BackgroundDalbergia sissoo DC. (Family: Fabaceae) is a medium to large deciduous tree, is locally called “shishu” in Bangladesh. It is used to treat sore throats, dysentery, syphilis, bronchitis, inflammations, infections, hernia, skin diseases, and gonorrhea. This study evaluated the antinociceptive effect of the methanol extract of D. sissoo leaves (MEDS) in mice.MethodsThe extract was assessed for antinociceptive activity using chemical and heat induced pain models such as hot plate, tail immersion, acetic acid-induced writhing, formalin, glutamate, and cinnamaldehyde test models in mice at the doses of 100, 200, and 400 mg/kg (p.o.) respectively. Morphine sulphate (5 mg/kg, i.p.) and diclofenac sodium (10 mg/kg, i.p.) were used as reference analgesic drugs. To confirm the possible involvement of opioid receptor in the central antinociceptive effect of MEDS, naloxone was used to antagonize the effect.ResultsMEDS demonstrated potent and dose-dependent antinociceptive activity in all the chemical and heat induced mice models (p < 0.001). The findings of this study indicate that the involvement of both peripheral and central antinociceptive mechanisms. The use of naloxone verified the association of opioid receptors in the central antinociceptive effect.ConclusionsThis study indicated the peripheral and central antinociceptive activity of the leaves of D. sissoo. These results support the traditional use of this plant in different painful conditions.

Evaluation of Chenopodium album Linn. Crude Methanolic Leaf Extract for Central Antinociceptive Activity in Albino Mice using the Hot Plate Test

The aim of study was to evaluate the crude leaf extract of Chenopodium album for central antinociceptive activity using inbred NIH albino mice. No mortalities were observed during the 14 day period in any of the 4 groups of 5 mice per group orally given 1, 2, 3, and 5 g/kg bw respectively. It was therefore assumed that the LD50 was higher than 5 g/kg bw. Eddy’s hot plate test for antinociception using 0, 50, 100 and 150 mg/kg bw and standard drug Aspirin (150 mg/kg bw) orally administered revealed that both Aspirin and the extract at 100 and at 150mg/kg bw exhibited significant (P < 0.05) dose-dependent antinociception compared with the negative control at the seven time intervals; 30, 60, 120,180, 240,300, 360 minutes. The maximum antinociception (71.47%) for the 150mg/kg bw group being at 30 minutes after administration and statistically not different from that of Aspirin (67.44%) at the same time interval. Between 30 and 180 minutes after oral administration of test substances, antinociception due to C. album extract (150 mg/kg bw) was statistically not different fromthatduetoAspirin. Thereafter Aspirin remained more efficacious than the extracttill the end of experiment at 360 minutes; a parallel shift from 240 minutes suggesting a similar mechanism of antinociception.

Peripheral and central antinociceptive effects of the butanolic fraction of Byrsonima verbascifolia leaves on nociception-induced models in mice.

Byrsonima verbascifolia (Malpighiaceae), commonly known as 'murici', is used in folk medicine, for example, in the treatment of inflammation. The anti-inflammatory activity of the butanolic fraction of B. verbascifolia leaves (BvBF) was previously reported by our group, and the present study was designed to evaluate their antinociceptive effects. BvBF (25, 50, and 100mg/kg) administered intraperitoneally (i.p.) inhibited acetic acid induced abdominal writhing. In the formalin test, BvBF (10, 30 and 100mg/kg, i.p.) caused a reduction in licking time in both the neurogenic and inflammatory phases. Moreover, we demonstrated that BvBF (30 and 100mg/kg, i.p.) caused an increase in the latency to response in the hot-plate test. These results demonstrate that BvBF possesses marked peripheral and central antinociceptive activities. Pre-treatment with the non-selective receptor antagonist naloxone (5mg/kg, i.p.) abolished the antinociceptive effects of BvBF (100mg/kg, i.p.) in the neurogenic phase of the formalin and hot-plate tests. The anti-inflammatory activity of BvBF (previously reported) as well as the participation of the opioidergic system seems to be responsible, at least in part, for these antinociceptive effects. Finally, BvBF at the doses investigated (25, 50 and 100mg/Kg) did not cause any toxicity signals, showing that the antinociceptive activity is devoid of sedative and hypomotility effects.

Antinociceptive Effect of 3-(2,3-Dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one in Mice Models of Induced Nociception.

The antinociceptive effects produced by intraperitoneal administration of a novel synthetic chalcone, 3-(2,3-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMFP), were investigated in several mouse models of induced nociception. The administration of DMFP (0.1, 0.5, 1.0 and 5.0 mg/kg) produced significant attenuation on the acetic acid-induced abdominal-writhing test. It also produced a significant increase in response latency time in the hot-plate test and a marked reduction in time spent licking the injected paw in both phases of the formalin-induced paw-licking test. In addition, it was also demonstrated that DMFP exhibited significant inhibition of the neurogenic nociceptive response induced by intraplantar injections of capsaicin and glutamate. Moreover, the antinociceptive effect of DMFP in the acetic acid-induced abdominal-writhing test and the hot-plate test was not antagonized by pretreatment with a non-selective opioid receptor antagonist, naloxone. Finally, DMFP did not show any toxic effects and/or mortality in a study of acute toxicity and did not interfere with motor coordination during the Rota-rod test. Our present results show that DMFP exhibits both peripheral and central antinociceptive effects. It was suggested that its peripheral antinociceptive activity is associated with attenuated production and/or release of NO and various pro-inflammatory mediators, while central antinociceptive activity seems to be unrelated to the opioidergic system, but could involve, at least in part, an interaction with the inhibition of capsaicin-sensitive fibers and the glutamatergic system.

Antinociceptive, Anti-inflammatory and Hypoglycemic Activities of Terminalia citrina Leaves

The present study was designed to investigate the antinociceptive, anti-inflammatory and hypoglycemic effects of petroleum ether, carbon tetrachloride, dichloromethane and ethyl acetate soluble partitionates of the methanolic extracts of Terminalia citrina leaves. The partitionates of the methanolic extract of the leaves of plant T. citrina at 200 mg/kg and 400 mg/kg were subjected for their antinociceptive activity using both acetic acid induced writhing method and radiant heat tail flicking method; anti-inflammatory activity was evaluated by HRBC membrane stabilization method and hypoglycemic activity by blood glucose level test. The carbon tetrachloride partitionate at 400 mg/kg induced significant decrease in the no. of writhes while the petroleum ether partitionate at 400 mg/kg showed promising activity compared to standard diclofenac sodium. Similarly, the petroleum ether partitionate elongates the reaction time significantly after administration of extract in radiant heat tail flicking method, suggesting central antinociceptive activity and at concentration of 2000 ?g/ml showed promising protection of HRBC in hypotonic solution compared with standard naproxen. On the other hand, in hypoglycemic activity, the ethyl acetate partitionate shows significant activity compared to standard metformin drug.Bangladesh Pharmaceutical Journal 19(1): 25-31, 2016

Central antinociceptive activity of peripherally applied botulinum toxin type A in lab rat model of trigeminal neuralgia.

BackgroundBoNT-A is often used in the clinical treatment for movement disorders. In recent years, various clinical studies suggest that BoNT-A can effectively alleviate pain caused by trigeminal neuralgia (TN); however, its mechanism remains unclear.MethodsIn this study, we used a lab rat model for TN produced by chronic constriction injury of the infraorbital nerve (ION-CCI). Restrained rats were injected subcutaneously with BoNT-A into the whisker pad tissue (ipsilaterally to the nerve injury) 14 days after the ION-CCI. Allodynia was tested by Von Frey filaments and TRPs and cSNAP-25 were tested by western blot.ResultsPeripheral application of BoNT-A (3, 10 U/kg) significantly increased the pain threshold of ION-CCI rats. Rota-rod test showed that BoNT-A administration at doses tested did not significantly affect rat motor coordination. By probing for a specific marker for BoNT-A, cleaved synaptosomal-associated protein 25 (cSNAP-25), we found that peripheral application of BoNT-A (10 U/kg) affected brainstem Vc, which could be blocked by the axonal transport blocker colchicine. In addition, western blot analysis showed that in the Vc region of ION-CCI rats, the expression levels of TRPA1, TRPV1, TRPV2 and TRPM8 increased, whereas peripheral application of BoNT-A significantly lowered the high expression of TRPA1, TRPV1 and TRPV2, but not TRPM8 at 7 days after BoNT-A injection.ConclusionsThe finding of this study suggest that peripherally applied BoNT-A can produce antinociceptive effects in ION-CCI model. The underlying mechanisms may be BoNT-A acts on the Vc via axonal transport, inhibits the high expression of TRPA1, TRPV1 and TRPV2, and reduces central sensitization.

Antinociceptive and anti-inflammatory effects of Memora nodosa and allantoin in mice

Ethnopharmacological relevanceThe leaves and stems bark of Memora nodosa (Silva Manso) Miers (Bignoniaceae) are used in Brazilian traditional medicine in the treatment of external ulcers and wounds; its roots are used to treat abdominal pain and scabies. Aim of the studyOur aim was to evaluate the antinociceptive and anti-inflammatory activities of Memora nodosa roots ethanolic extract (EMN) and allantoin, a secondary metabolite isolated from this plant. Materials and methodsThe EMN and allantoin antinociceptive activity were evaluated in mice using both chemical and heat-induced pain models such as acetic acid-induced writhing, formalin and tail-flick tests. In the formalin test, a pre-treatment with naloxone was used to verify an involvement of opioid receptor in the antinociceptive effect of EMN and allantoin. Pre-treatment with glibenclemide was used to verity an involvement of ATP-sensitive K+channel in the allantoin antinociceptive effect. EMN and allantoin anti-inflammatory activity were assessed by carrageenan-induced paw edema and pleurisy tests. ResultsThe treatment with EMN (250, 500 and 1000mg/kg, p.o.) inhibit the acetic acid and formalin (both phases)-induced nociception. However, just at doses 500 and 1000mg/kg increased the latency time in tail-flick test. These results suggest the involvement of both peripheral and central antinociceptive mechanisms. The treatment with allantoin (40, 60 and 80mg/kg p.o.) produced a dose-dependent antinociceptive effect in both phases of formalin-induced nociception test; allantoin (60mg/kg) was not able to increase the latency time in tail flick-test. The pre-treatment with naloxone completely reversed the EMN (1000mg/kg) and allantoin (60mg/kg) effect in the first phase of formalin test; and glibenclamide reversed the allantoin effect. The administration of EMN (250, 500 and 1000mg/kg) and allantoin (60mg/kg) showed significant anti-inflammatory activity in the whole carrageenan-induced paw edema. Furthermore, EMN and allantoin reduced the leukocytes migration and pleural exudate to the pleural cavity. ConclusionEMN have significant antinociceptive and anti-inflammatory effects, which appear to be, at least in part, due to the presence of allantoin. However, allantoin is not responsible for the EMN central antinociceptive activity. Allantoin has peripheral antinociceptive activity that involves the opioid receptor and ATP-sensitive K+channels. Opioid receptors are also involved in the EMN antinociceptive activity. These findings support the use of Memora nodosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of antinociceptive and anti-inflammatory phytomedicines.

Evaluation of antinociceptive and antidiarrhoeal properties of Manilkara zapota leaves in Swiss albino mice

Context Manilkara zapota (L.). P. Royen. (Sapotaceae) has been used in folk medicine to treat pain, diarrhoea, inflammation, arthralgia, and other disorders.Objective Screening of Manilkara zapota leaves ethanol extract and its different solvent soluble fractions for possible antinociceptive and antidiarrhoeal activities in Swiss albino mice.Materials and methods The extract and various fractions (200 and 400 mg/kg body weight; p.o.) were tested for peripheral and central antinociceptive activity by acetic acid-induced writhing and radiant heat tail-flick method, respectively; castor oil-induced diarrhoeal model was used to evaluate antidiarrhoeal activity at both doses. All the samples were administered once in a day and the duration of study was approximately 5 h.Results Ethanol extract (400 mg/kg), petroleum ether fraction (400 mg/kg), and ethyl acetate fraction (400 mg/kg) showed significant peripheral antinociceptive activity having 59.89, 58.24, and 46.7% (p < 0.001) of writhing inhibition, respectively, which is comparable with that of standard diclofenac (59.34% inhibition). The ethanol extract (400 mg/kg) and petroleum ether fraction (400 mg/kg) also showed promising central analgesic activity having 74.15 and 82.15% (p < 0.001) elongation of reaction time, respectively, at 90 min after administration of sample which is also similar to that obtained by morphine (85.84% elongation). In antidiarrhoeal activity screening, ethanol extract (200 and 400 mg/kg) showed significant inhibition of defecation by 53.57 and 60.71%, respectively (p < 0.001) compared with that of loperamide (71.42%).Discussion and conclusion The findings of the studies demonstrated antinociceptive and antidiarrhoeal activities of M. zapota leaves which could be the therapeutic option against pain and diarrhoeal disease.

Synthesis and antinociceptive activity of methyl nicotinate

Methyl nicotinate (methyl-3-pyridinecarboxylate) is a methyl ester of nicotinic acid – a type of B vitamin called niacin. It was prepared by esterification of nicotinic acid by refluxing with methanol in the presence of concentrated sulphuric acid, esterification product obtained was extracted into organic solvent (chloroform) after neutralization of the reaction mixture with 10% sodium bicarbonate. The product was purified by column chromatography and purity ascertained by thin layer chromatography. Structure of the desired product was confirmed by NMR and Mass spectroscopy. Methyl nicotinate was obtained as a white powder (m.p. 40-42oC, 23.39% yield). The product was evaluated for its antinociceptive activity using the acetic acid-induced writhing and the hot plate test in mice. The synthesized compound exhibited effective peripheral and central antinociceptive activity. Oral doses of methyl nicotinate (5 and 10 mg/kg) caused a significant reduction in the number of writhes induced by acetic acid (P &lt; 0.05) and prolonged the reaction latency to thermally-induced pain in mice.Keywords: Methyl nicotinate, esterification, antinociceptive activity

Rationale for use of onabotulinum toxin A (BOTOX) in chronic migraine.

Chronic migraine is a severely disabling headache evolving from episodic migraine as a result of different transforming factors and characterized by atypical pain modulation and peripheral and central sensitization. Discovered by serendipity, onabotulinum toxin A (BoNT-A) represents the only drug specifically approved for CM prophylaxis. According to the dominant opinion, BoNT-A acts peripherally, impairing the exocytosis of neuropeptide and neurotransmitter and the delivery of receptors and ion channels on the cell surface of peripheral trigeminal endings, thereby indirectly reducing central sensitization. However, it is not excluded that BoNT-A has also a central antinociceptive action, probably associated with an enhanced opioidergic and GABA-ergic transmission. This review discusses the rationale for use of BoNT-A in CM including its mechanisms of action and molecular targets and provides suggestions for a more tailored BoNT-A prophylaxis in patients with CM.

Molecular docking, isolation and biological evaluation of Rhizophora mucronata flavonoids as anti-nociceptive agents

The anti-nociceptive effect of Rhizophora mucronata was evaluated on chemically and thermally induced nociception in mice. Albino mice received a dose of 10, 15, 20, or 25mg/kg of alkaline chloroform fraction (Alk-CF) of R. mucronata by oral administration. Compared with controls, Alk-CF decreased the writhing numbers (P<0.01) in a dose-dependent manner. Further, we determined that Alk-CF contained, a potent compared to control, also potent anti-nociceptive agent that acted via opioid receptors and using HPLC, identified this compound as luteolin. Docking simulation demonstrated that luteolin interacted strongly with cyclooxygenase, forming a number of specific hydrogen bonds. This study identified peripheral and central anti-nociceptive activities of R. mucronata that involve opioid receptor, and in which the active compound is luteolin as a source of new anti-nociceptive agent.

In-vivo antinociceptive, anti-inflammatory and antipyretic activity of pistagremic acid isolated from Pistacia integerrima

The current study was designed to explore the antinociceptive, antiinflammatory and antipyretic activity of pistagremic acid (PA), isolated from Pistacia integerima bark in various animal paradigms. The results illustrated significant inhibition of noxious stimulation in acetic acid induced writhing test with maximum effect of 68% at 10mg/kg i.p. In tail immersion test, pretreatment with PA demonstrated marked activity during various assessment times in a dose dependent manner. The maximum pain inhibition was 59.46% at 10mg/kg i.p. after 90min of PA treatment. However, the injection of naloxone did not antagonize this induced effect. PA significantly ameliorated post carrageenan induced edema dose dependently during various stages of inflammation. The effect was most dominant (60.02%) after 3rd h of drug administration when examined for 5h. Similarly, it provoked dose dependent antipyretic effect in febrile mice with maximum of 60.04% activity at 10mg/kg i.p. after 3rd hour of PA post treatment. Furthermore, molecular docking was carried out to understand the binding mode of PA. From the docking study it was observed that PA fits well in the active site of COX-2 enzyme due to hydrogen and hydrophobic moiety interactions to the important active site of molecule.In conclusion, PA possesses strong peripheral and central antinociceptive activity independent of opioidergic effect which was augmented by its anti-inflammatory and antipyretic activities.

Minocycline encapsulated chitosan nanoparticles for central antinociceptive activity

The purpose of the study is to explore the central anti-nociceptive activity of brain targeted nanoparticles (NP) of minocycline hydrochloride (MH). The NP were formulated using the modified ionotropic gelation method (MHNP) and were coated with Tween 80 (T80) to target them to brain (cMHNP). The formulated nanoparticles have already been characterized for particle size, zeta potential, drug entrapment efficiency and in vitro drug release. The nanoparticles were then evaluated for pharmacodynamic activity using thermal methods. The pure drug and the formulation, MHNP were not able to show a statistically significant central analgesic activity. cMHNP on the other hand evidenced a significant central analgesic activity. Animal models evidenced that brain targeted nanoparticles may be utilized for effective delivery of central anti-nociceptive effect of MH. Further clinical studies are required to explore the activity for mankind.

Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin-sensitive neurons

Unlike most classical analgesics, botulinum toxin type A (BoNT/A) does not alter acute nociceptive thresholds, and shows selectivity primarily for allodynic and hyperalgesic responses in certain pain conditions. We hypothesized that this phenomenon might be explained by characterizing the sensory neurons targeted by BoNT/A in the central nervous system after its axonal transport. BoNT/A’s central antinociceptive activity following its application into the rat whisker pad was examined in trigeminal nucleus caudalis (TNC) and higher-level nociceptive brain areas using BoNT/A-cleaved synaptosomal-associated protein 25 (SNAP-25) and c-Fos immunohistochemistry. Occurrence of cleaved SNAP-25 in TNC was examined after nonselective ganglion ablation with formalin or selective denervation of capsaicin-sensitive (vanilloid receptor-1 or TRPV1-expressing) neurons, and in relation to different cellular and neuronal markers. Regional c-Fos activation and effect of TRPV1-expressing afferent denervation on toxin’s antinociceptive action were studied in formalin-induced orofacial pain.BoNT/A-cleaved SNAP-25 was observed in TNC, but not in higher-level nociceptive nuclei. Cleaved SNAP-25 in TNC disappeared after formalin-induced trigeminal ganglion ablation or capsaicin-induced sensory denervation. Occurrence of cleaved SNAP-25 in TNC and BoNT/A antinociceptive activity in formalin-induced orofacial pain were prevented by denervation with capsaicin. Cleaved SNAP-25 localization demonstrated toxin’s presynaptic activity in TRPV1-expressing neurons. BoNT/A reduced the c-Fos activation in TNC, locus coeruleus, and periaqueductal gray.Present experiments suggest that BoNT/A alters the nociceptive transmission at the central synapse of primary afferents. Targeting of TRPV1-expressing neurons might be associated with observed selectivity of BoNT/A action only in certain types of pain.

Antinociceptive effect of the essential oil of tarragon (Artemisia dracunculus)

Context: Tarragon [Artemisia dracunculus L. (Asteraceae)] is used as a commercial flavoring and in perfumery. In traditional folk medicine, tarragon has been used for treatment of pain and gastrointestinal disturbances.Objective: This study investigated the antinociceptive effect of the essential oil of A. dracunculus (EOAD) in various experimental models.Materials and methods: The median lethal dose (LD50) of EOAD was estimated using the method of Lorke. The antinociceptive effect was assessed using chemical (formalin and acetic acid) and thermal (hot-plate) nociceptive tests in rats and mice. In all experiments, EOAD was administered intraperitoneally at the doses of 10, 30, 100 and 300 mg/kg.Results: In the acute toxicity test, the value of estimated LD50 for EOAD was 1250 mg/kg. EOAD (100 and 300 mg/kg) significantly reduced (p < 0.001) the pain response in the first (59.5 and 91.4%) and second (52.5 and 86.3%) phases of the formalin test, respectively. Central involvement in analgesic profile was confirmed by the hot-plate test, in which the EOAD showed a significant analgesic activity by increasing latency time. EOAD (10, 30, 100 and 300 mg/kg) significantly (p < 0.001) inhibited (89, 95, 97 and 97%) the nociception produced by acetic acid. Naloxone failed to antagonize the antinociceptive effect of the essential oil in the acetic acid-induced writhing test. It seems that mechanism(s) other than opioid receptors is (are) involved in the analgesic effect of EOAD.Conclusions: This study reported the peripheral and central antinociceptive activity of the EOAD and rationalized the traditional use of the plant in the treatment of different painful conditions.