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The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K + channel opening in the formalin test. Wistar rats (180-220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50-200 μg/paw) or buprenorphine (1-5 μg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (N G -nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the K ir 6.1-2, ATP-sensitive K + channel inhibitors (glibenclamide and glipizide), by the K Ca 2.1-3, small conductance Ca 2+ -activated K + channel blocker (apamin), by the K Ca 1.1, large conductance Ca 2+ -activated K + channel blocker (charybdotoxin), and by the K V , voltage-dependent K + channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.

β-Sitosteryl (S)-ibuprofenate (2), stigmasteryl (S)-ibuprofenate (3), ergosteryl (S)-ibuprofenate (4), and cholesteryl (S)-ibuprofenate (5) were prepared in 70-75% yields by Steglich esterification and were characterized by 1D and 2D NMR, as well as by MS. The new esters were evaluated in in vivo pain models of antinociception and anti-inflammation using the writhing, formalin, and carrageenan tests, in mice and rats, and the results were compared with those of (S)-ibuprofen (1). Damage to the gastric mucosa of animals was also assessed. The results indicated that 2-5 have comparable or eventually better activity than 1 at the same mg/kg doses. Since the molecular weight ratio of esters 2-5 to ibuprofen is about 3-1, the amount of truly incorporated ibuprofen was roughly one third to achieve similar effects. This resulted in minimal gastrointestinal damage in the stomach of the animals, in contrast to the large gastric injury caused by (S)-ibuprofen., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Preclinical Research The aim of this work was to evaluate the effect of docosahexaenoic acid (DHA) on the pharmacokinetics and pharmacodynamics-nociception-of naproxen in rats, as well as to determine the gastric safety resulting from this combination versus naproxen alone. Female Wistar rats were orally administered DHA, naproxen or the DHA-naproxen mixture at fixed-ratio combination of 1:3. The antinociceptive effect was evaluated using the formalin test. The gastric injury was determined 3 h after naproxen administration. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and naproxen. To determine the possibility of pharmacokinetic interactions, the oral bioavailability of naproxen was evaluated in presence and absence of oral DHA. The experimental effective dose ED 30 values (Zexp) were decreased from theoretical additive dose values (Zadd; P < 0.05). The isobolographic analysis showed that the combination exhibited supra-additive interaction. The oral administration of DHA increased the pharmacokinetic parameter AUC 0- of naproxen (P < 0.05). Furthermore, the gastric damage induced by naproxen was abolished when this drug was combined with DHA. These data suggest that oral administration of DHA-naproxen combination induces gastric safety and supra-additive antinociceptive effect in the formalin test so that this combination could be useful to management of inflammatory pain. Drug Dev Res 78 : 332-339, 2017. © 2017 Wiley Periodicals, Inc.t of naproxen (P < 0.05). Furthermore, the gastric damage induced by naproxen was abolished when this drug was combined with DHA. These data suggest that oral administration of DHA-naproxen combination induces gastric safety and supra-additive antinociceptive effect in the formalin test so that this combination could be useful to management of inflammatory pain. Drug Dev Res 78 : 332-339, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Geranium bellum Rose, locally known as "Pata de león", is a perennial plant distributed in the mountains of Hidalgo, Mexico. It is widely used in Mexican traditional medicine to treat fever, pain, and gastrointestinal disorders. To date, there are not published studies regarding the in vivo antinociceptive and anti-inflammatory potential of the acetone-aqueous extract from the aerial parts of G. bellum., Methods: Antinociceptive effects of the acetone-aqueous G. bellum (AGB) extract and the isolated compounds were assessed using experimental pain models, including thermal nociception like hot plate test, and chemical nociception induced by intraperitoneal acetic acid or subplantar formalin injection in vivo. The anti-inflammatory properties of the extract were studied using systemic administration in carrageenan-induced paw edema., Results: Intra-gastric administration of AGB (75, 150, and 300 mg/kg) showed a dose-dependent antinociceptive effect in intraperitoneal acetic acid (writhing), thermal nociception in CD1 mice, and subplantar formalin models, as well as anti-inflammatory effect in carrageenan- induced paw edema in Wistar rats. Geraniin and quercetin showed the highest antinociceptive activity in writhing test, whereas ellagic acid was the most active compound in the hot plate model., Conclusion: These studies provide evidences that G. bellum shows antinociceptive and anti- inflammatory effects, and gives support to its use in treating pain in Mexican traditional medicine.

The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1-31 mg/kg), curcumin (3.1-100 mg/kg) or the diclofenac-curcumin combination (2.4-38.4 mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10 mg/kg) was studied in presence and the absence of curcumin (31 mg/kg). Diclofenac, curcumin, or diclofenac-curcumin combination produced an antinociceptive effect on the formalin test. ED30 values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical ED30 for the antinociceptive effect (19.2 mg/kg) was significantly different from the observed experimental ED30 value (9.8 mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac-curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Background: There is evidence that biguanides and sulfonylureas block diclofenac-induced antinociception (DIA) in rat models. However, little is known about the interaction between these hypoglycemics with respect to DIA., Objective: To determine whether metformin-sulfonylurea combinations affect DIA during the formalin test., Methods: Rats received the appropriate vehicle or diclofenac before 1% formaldehyde was injected into the paw. Rats were also pretreated with vehicle, glibenclamide, glipizide, metformin or glibenclamide⁄metformin and glipizide⁄metformin combinations before the diclofenac and formaldehyde injections, and the effect on antinociception was assessed. Isobolograms of the combinations were constructed to test for a synergistic interaction., Results: Systemic injection of diclofenac resulted in antinociception during the second phase of the test. Systemic pretreatment with the combinations of glibenclamide (0.56 mg⁄kg to 10 mg⁄kg)⁄metformin (10 mg⁄kg to 180 mg⁄kg) and glipizide (0.56 mg⁄kg to10 mg⁄kg)⁄metformin (10 mg⁄kg to 180 mg⁄kg) blocked DIA. The derived theoretical effective doses for 50% of subjects (ED50) for the glibenclamide⁄metformin and glipizide⁄metformin combinations were 32.52 mg⁄kg and 32.42 mg⁄kg, respectively, and were significantly higher than the actual observed experimental ED50 values (7.57 mg⁄kg and 8.43 mg⁄kg, respectively)., Conclusion: Pretreatment with glibenclamide, glipizide or metformin blocked DIA in a dose-dependent manner, and combining either sulfonylurea with metformin produced even greater effects. The observed ED50s for the combinations were approximately fourfold lower than the calculated additive effects. These data indicate that sulfonylureas interact to produce antagonism of DIA. Combination therapy is a common second-line treatment for patients with diabetes and metabolic syndrome, a group that experiences pain from multiple sources. The results suggest that at least some anti-inflammatory agents may not be effective in this group.

Aim: This article is a report of a study carried out to investigate the procedures that are likely to induce pain and anxiety in children in a Mexican emergency department., Background: In emergency rooms, children often experience unpredictable diagnostic and therapeutic procedural-related pain that can be associated with considerable anxiety., Design: A prospective, descriptive and cross sectional study was conducted to investigate the prevalence of procedures or situations that probably induced anxiety and/or pain in children in an emergency room., Methods: Procedural pain and anxiety were evaluated in children and adolescents (8-16 years) who were admitted to the emergency department of a paediatric hospital between February-September 2010. Children rated their pain and anxiety using a 100-mm visual analogue scale., Results: A total of 252 children with a mean age of 10·1 years were evaluated. Four-hundred fifty-nine procedures were completed, with an average of 1·82 events/child. Of these procedures, 369 (80·4%) were rated painful and 357 (77·8%) were rated stressful. The most frequently reported procedural pain or stressful episodes were peripheral catheterization, clinical examination and vascular puncture. Overall, 32·5% of the painful events were rated severe, 32·0% were rated moderate and 35·5% were rated slight. However, 30% of the stressful events were rated severe, 38·9% were rated moderate and 31·1% were rated slight. Peripheral catheterization was rated severe in 58 children (33·9%), moderate in 55 children (32·2%) and slight in 58 (33·9%) children., Conclusion: This study provides data on common emergency department procedures that cause pain and anxiety in children and young adolescents. Healthcare providers must consider the best psychological and pharmacological interventions to reduce procedural anxiety and pain., (© 2012 Blackwell Publishing Ltd.)

The model-based approach was undertaken to characterize the interaction between the peripheral and central antinociceptive effects exerted by lumiracoxib. The effects of intraplantar and intrathecal administrations and of fixed ratio combinations of lumiracoxib simultaneously administered by these two routes were evaluated using the formalin test in rats. Pain-related behavior data, quantified as the number of flinches of the injected paw, were analyzed using a population approach with NONMEM 7. The pain response during the first phase of the formalin test, which was insensitive to lumiracoxib, was modeled using a monoexponential decay. The second phase, which was sensitive to lumiracoxib, was described incorporating synthesis and degradation processes of pain mediators that were recruited locally after tissue injury. Upregulation at the local level and in the central nervous system (CNS) was set to be proportional to the predicted levels of pain mediators in the local (injured) compartment. Results suggest a greater role of upregulated COX-2(Local) in generating the pain response compared to COX-2(CNS). Drug effects were described as inhibition of upregulated COX-2. The model adequately described the time course of nociception after formalin injection in the absence or presence of lumiracoxib administered locally and/or spinally. Data suggest that the overall response is the additive outcome of drug effects at the peripheral and central compartments, with predominance of peripheral mechanisms. Application of modeling opens new perspectives for understanding the overall mechanism of action of analgesic drugs.

Ethnopharmacological Relevance: H. longipes S.F. Blake (Asteraceae) is a Mexican plant, whose roots are traditionally used as a condiment, as a mouth anesthetic, and as an antiparasitic. Affinin is the alkamide present in higher amounts in the roots of H. longipes., Aim of the Study: To date, there are no published studies regarding the relation between the analgesic properties, in vivo cytotoxicity, and DNA-damaging potential of H. longipes ethanol extract (HLEE)., Materials and Methods: The HLEE was chromatographically fingerprinted to validate its affinin contents. Biological evaluation was conducted in sets of 6-8 CD1(+) mice. Antinociceptive effect was evaluated using the writhing and hot-plate tests, and mutagenic and cytotoxic effects were evaluated with micronucleous test in CD1(+) mice. For histopathological studies, biological samples from liver, heart, kidneys, spleen, lung, and brain were collected and stained., Results: Oral administration of HLEE (3-100 mg/kg) produced a dose-dependent antinociceptive effect in both assays. In micronucleus assay, the variability in the number of micronucleated polychromatic erythrocytes (MNPE) induced, and PE/NE index, the ratio of polychromatic erythrocytes with respect to the number of normochromatic erythrocytes induced by HLEE in the evaluated schedule, were small and nonsignificant. After histopathological results, HLEE showed polioencephalomalacia with 1000 mg/kg dose., Conclusions: This work provides evidence that HLEE exerts analgesic effects, with no genotoxic effects in vivo. These findings would be an important contribution to explain the use of H. longipes root as an effective analgesic in traditional medicine, and to establish for the first time the absence of genotoxic and cytotoxic effects of the root in bioactive doses in vivo., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of acute gout and inflammation. However, its use is limited due to side effects. Acemetacin is a prodrug of indomethacin that exhibits better gastric tolerability in preclinical and clinical trials. The aim of this study was to examine if the systemic administration of acemetacin involved the sequential participation of nitric oxide (NO) or K+ channel pathways to confer its antinociceptive effect, as compared to indomethacin. The antinociceptive effect of both drugs was studied with the formalin test. Equimolar doses of acemetacin or indomethacin were administered orally. The intraplantar administration of either L-NAME, glibenclamide, apamin or charybdotoxin plus indomethacin or acemetacin was studied using the formalin test and the anti-inflammatory and antihyperalgesic effects were measured. The antinociceptive effect of acemetacin or indomethacin was not significantly different when pretreatment with L-NAME, glibenclamide, apamin or charybdotoxin was done. The antihyperalgesic and antiinflammatory effects were also similar for both indomethacin and acemetacin. Our results suggest that the antinociceptive effect of indomethacin or acemetacin is not mediated by NO or K+ channel activation., (2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

The possible participation of K+ channels in the antinociceptive action of meloxicam was assessed in the 1% formalin test. Local peripheral administration of meloxicam produced a dose-dependent antinociception only during the second phase of the formalin test. K+ channel blockers alone did not modify formalin-induced nociceptive behavior. However, local peripheral pretreatment of the paw with charybdotoxin and apamin (large- and small-conductance Ca2+-activated K+ channel inhibitors, respectively), 4-aminopyridine and tetraethylammonium (non-selective voltage-dependent K+ channel inhibitors), but not glibenclamide or tolbutamide (ATP-sensitive K+ channel inhibitors), dose-dependently prevented meloxicam-induced antinociception. It is concluded that meloxicam could open large- and small-conductance Ca2+-activated K+ channels, but not ATP-sensitive K+ channels, in order to produce its peripheral antinociceptive effect in the formalin test. The participation of voltage-dependent K+ channels was also suggested, but since non-selective inhibitors were used the data await further confirmation.