Thermal Pain Models Research Articles

Antinociceptive effect of novel trihalomethyl-substituted pyrazoline methyl esters in formalin and hot-plate tests in mice

The aim of the present study was to evaluate the antinociceptive potential of four novel pyrazoline methyl ester compounds on chemical and thermal models of pain in mice. The following 5-trihalomethylated-4,5-dihydro-1 H-pyrazole methyl ester compounds were tested: 3-methyl-5-trifluoromethyl-(MPF3), 4-methyl-5-trifluoromethyl-(MPF4), 3-methyl-5-trichloromethyl-(MPCl3) and 4-methyl-5-trichloromethyl-(MPCl4). MPF3, MPF4, MPCl3 and MPCl4 (0.03-1.0 mmol/kg) given intraperitoneally decreased neurogenic and inflammatory phases of nociception in the formalin test. Moreover, MPF3, MPF4, MPCl3, MPCl4 (0.1-1.0 mmol/kg) and dipyrone (1.5 mmol/kg) also produced a dose-dependent antinociceptive effect in the hot-plate test. However, MPF3, MPF4, MPCl3 and MPCl4 did not impair motor coordination in the rotarod test or spontaneous locomotion in the open field test. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was reversed by the opioid receptor antagonist naloxone (2 mg/kg, i.p.), but not by the alpha 2-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or by p-chlorophenylalanine ethyl ester (PCPA, 300 mg/kg, i.p.) treatment. In contrast to morphine (5 mg/kg, i.p.), MPF4 given daily for up to 8 days did not generate a tolerance to its antinociceptive effect. However, similar to morphine (11 mg/kg, i.p.), MPF4 reduced gastrointestinal transit in mice. Taken together these results demonstrate that these novel pyrazoline methyl esters tested may be promising prototypes of additional mild analgesics.

Functional blockage of the cannabinoid receptor type 1 evokes a kappa‐opiate‐dependent analgesia

Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor type 1 (CB1-R) inhibition in nociception, we performed a subchronic administration of the CB1-R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) in mice. This treatment provoked analgesia in peripheral thermal and visceral models of pain. Analysis of genes encoded for the opioid system in the spinal cord showed an increase in the expression of genes encoded for the κ-opioid system in AM281-injected mice compared with vehicle-injected ones. Furthermore, systemic administration of nor-binaltorphimine, a κ-opioid receptor antagonist, blocked AM281-induced analgesia. Finally, c-fos expression in the dorsal spinal cord and higher centers of pain processing after noxious stimulation were significantly lower in AM281-injected mice than in vehicle-injected animals, indicating that dynorphin could block nociceptive information transmission at the spinal cord level. These results indicate the existence of a cross-talk between opioid and cannabinoid systems in nociception. Furthermore, the results suggest that CB1-R antagonists could be useful as a new therapeutic approach for pain relief.

Antinociceptive action of ethanolic extract obtained from roots of Humirianthera ampla Miers

Humirianthera ampla Miers is a member of the Icacinaceae family and presents great amounts of di and triterpenoids. These chemical constituents in roots of Humirianthera ampla sustain not only the ethnopharmacological use against snake venom, but also some anti-inflammatory and analgesic properties of the plant. In this study we investigated the antinociceptive action of the ethanolic extract (EE) from roots of the Humirianthera ampla in chemical and thermal models of pain in mice. The oral treatment with ethanolic extract dose-dependently inhibited glutamate-, capsaicin- and formalin-induced licking. However, it did not prevent the nociception caused by radiant heat on the tail-flick test. The ethanolic extract (30 mg/kg) caused marked inhibition of the nociceptive biting response induced by glutamate, (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (trans-ACPD), N-methyl- d-aspartate (NMDA) and substance P. The antinociception caused by ethanolic extract was significantly attenuated by naloxone, l-arginine, WAY100635, ondansetron or ketanserin, but not by caffeine or naloxone methiodide. In conclusion, the ethanolic extract from roots of Humirianthera ampla produces antinociception against neurogenic and inflammatory models of nociception. The mechanisms of antinociception involve nitric oxide, opioid, serotonin and glutamate pathways. Therefore, our results support the ethnopharmacological use of the Humirianthera ampla against inflammatory and painful process caused by snake venom.

A-366833: A novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane α4β2 nicotinic acetylcholine receptor selective agonist: Synthesis, analgesic efficacy and tolerability profile in animal models

5-[(1 R,5 S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([ 3H]-cytisine) with K i value of 3.1 nM and exhibits agonist selectivity at α4β2 nAChR relative to the α3β4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 μmol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2–19.0 μmol/kg, i.p.), formalin (1.9–19 μmol/kg i.p.) and SNL (1.9–19 μmol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 μmol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5 h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at α4β2 vs. α3β4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.

Analgesic activity of Ugni molinae (murtilla) in mice models of acute pain

Leaf extracts of Ugni molinae Turcz. (Myrtaceae) are used in Chilean folk medicine as analgesic and anti-inflammatory. The antinociceptive effect of dichloromethane (DCM), ethyl acetate (EA) and methanol (ME) leaf extracts was assessed by intraperitoneal, oral and topical administration in writhing, tail flick, and tail formalin tests in mice. The extracts showed a dose-dependent antinociceptive activity in all the assays under different administration routes. The ED 50 values for the different tests for the DCM, EA, ME extract and reference drug (ibuprofen) were as follows. Writhing test in acetic acid (i.p. administration): 0.21, 0.37, 1.37 and 0.85 mg/kg, respectively; tail flick test (oral administration): 199, 189, 120 and 45.9 mg/kg. The EC 50 values for tail flick test were (topical administration): 2.0, 0.35, 1.4 and 8.2% (w/v), respectively; and the topical analgesic effects were (formalin assay) 75.5, 77.5, 31.6 and 76.5%, respectively. Ugni molinae extracts produce antinociception in chemical and thermal pain models through a mechanism partially linked to either lipooxygenase and/or cyclooxygenase via the arachidonic acid cascade and/or opioid receptors. Flavonoid glycosides and triterpenoids have been isolated from the plant and can be associated with the observed effect. Our results corroborate the analgesic effects of Ugni molinae, and justify its traditional use for treating pain.

Analysis of the antinociceptive effect of the proanthocyanidin-rich fraction obtained from Croton celtidifolius barks: Evidence for a role of the dopaminergic system

In a previous study, we demonstrated the antinociceptive effect of 63SF, a proanthocyanidin-rich fraction obtained from Croton celtidifolius barks, in chemical and thermal behavioural models of pain in mice. The current study now investigate the possible mechanisms underlying the antinociceptive activity of 63SF in the formalin test, by using drugs which interfere with systems that are implicated in descending control of nociception. The antinociceptive effect of 63SF (11 mg/kg, i.p., given 30 min prior to 2.5% formalin) was not altered by pre-treatment of animals 45–50 min beforehand with either prazosin (α 1-adrenergic antagonist; 0.15 mg/kg, i.p.), yohimbine (α 2-adrenergic antagonist; 0.15 mg/kg, i.p.), ketanserin (5-HT 2A-receptor antagonist; 1.0 mg/kg, i.p.), or l-arginine (substrate for NO synthase, 600 mg/kg, i.p.). On the other hand, treatment with sulpiride, an antagonist of dopaminergic D 2-receptors (1.0 mg/kg, i.p., 45 min of pre-treatment), reversed the antinociceptive activity of 63SF. Pre-treatment of animals with reserpine (5 mg/kg, i.p., 24 h beforehand) did not alter the antinociceptive effect of 63SF. The current results support the view that the 63SF exerts antinociceptive effects by enhancing the activity of descending control, possibly by direct stimulation of dopaminergic D 2 receptors.

Morphine, Oxycodone, Methadone and Its Enantiomers in Different Models of Nociception in the Rat

We studied the effects of the commonly used mu-opioid receptor agonists morphine, oxycodone, methadone and the enantiomers of methadone in thermal and mechanical models of acute pain and in the spinal nerve ligation model of neuropathic pain in rats. Subcutaneous administration of morphine, oxycodone, and methadone produced a dose-dependent antinociceptive effect in the tail flick, hotplate, and paw pressure tests. l-methadone, racemic methadone, and oxycodone had a similar dose-dependent antinociceptive effect, whereas the dose-response curve of morphine was shallower. In the spinal nerve ligation model of neuropathic pain, subcutaneous administration of morphine, oxycodone, methadone and l-methadone had antiallodynic effects in tests of mechanical and cold allodynia. l-methadone showed the strongest antiallodynic effect of the tested drugs. d-methadone was inactive in all tests. Morphine 5.0 mg/kg, oxycodone 2.5 mg/kg, and l-methadone 1.25 mg/kg decreased spontaneous locomotion 30 min after drug administration. In conclusion, in acute nociception all mu-opioid receptor agonists produced antinociception, with morphine showing the weakest effect. In nerve injury pain, l-methadone showed the greatest antiallodynic potency in both mechanical and cold allodynia compared with the other opioids. Opioids seem to have different profiles in different pain models. l-methadone should be studied for neuropathic pain in humans.

The involvement of nitric oxide on the analgesic effect of tramadol

The involvement of nitric oxide on the analgesic effect of tramadol

Antinociceptive properties of the ethanolic extract and of the triterpene 3β,6β,16β-trihidroxilup-20(29)-ene obtained from the flowers of Combretum leprosum in mice

The present study examined the antinociceptive effects of the ethanolic extract (EE) and of the triterpene 3β,6β,16β-trihidroxilup-20(29)-ene obtained from the flowers of Combretum leprosum in chemical and thermal behavioural models of pain in mice. The EE (10–1000 mg/kg) given orally (p.o.), 1 h prior to testing, produced dose-dependent inhibition of acetic acid-induced visceral pain, with mean ID 50 value of 131.9 mg/kg. In the formalin test, the EE (10–300 mg/kg, p.o.) also caused significant inhibition of both the early (neurogenic pain) and the late (inflammatory pain) phases of formalin-induced licking, however, it was more potent and efficacious in relation to the late phase of the formalin test, with mean ID 50 values for the neurogenic and the inflammatory phases of ∼300 and 88.8 mg/kg, respectively. The EE (10–1000 mg/kg, p.o.) also caused significant and dose-dependent inhibition of capsaicin- and glutamate-induced pain, with mean ID 50 values of 160.5 and 38.3 mg/kg, respectively. Furthermore, the triterpene 3β,6β,16β-trihidroxilup-20(29)-ene (1–30 mg/kg), given p.o., 1 h prior to testing, also produced dose-related inhibition of glutamate-induced pain, with a mean ID 50 value of 5.6 mg/kg. When assessed in a thermal model of pain, the EE (10–300 mg/kg, p.o.) and fentanyl (100 μg/kg, s.c.) caused a significant and marked increase in the latency response on the hot-plate test (50 °C). The antinociception caused by EE (100 mg/kg, p.o.) in the glutamate test was significantly attenuated by intraperitoneal (i.p.) treatment of mice with naloxone (opioid receptor antagonist, 1 mg/kg), pindolol (a 5-HT 1A/1B receptor/β adrenoceptor antagonist, 1 mg/kg), WAY100635 (a 5-HT 1A receptor antagonist, 0.7 mg/kg) or ketanserin (a 5-HT 2A receptor antagonist, 0.3 mg/kg). In contrast, EE (100 mg/kg, p.o.) antinociception was affected neither by l-arginine (precursor of nitric oxide, 600 mg/kg) nor by ondansetron (a 5-HT 3 receptor antagonist, 0.5 mg/kg) i.p. treatment. It was not associated with non-specific effects such as muscle relaxation or sedation. Together, these results indicate that EE produces dose-related antinociception in several models of chemical and thermal pain through mechanisms that involve an interaction with opioid and serotonergic (i.e., through 5-HT 1A/1B and 5-HT 2A receptors) systems.

Antinociceptive effect of proanthocyanidins from Croton celtidifolius bark

The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0+/-2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g.catechin-(4alpha-->8)-catechin and gallocatechin-(4alpha-->8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value)=0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50=13.0 (10.0-17.0)), glutamate (ID50=4.0 (2.0-7.0)) and formalin (ID50 first phase=36.0 (24.0-53.0) and late phase=11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase=125.0 (89.0-177.0) and late phase=65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.

Spinal CK2 regulates nociceptive signaling in models of inflammatory pain

Casein kinase 2 (CK2) is a widely expressed protein kinase. Over the last several years a long list of protein substrates has evolved, many of which have proven or hypothesized roles in nociceptive signal transmission. However, CK2 has not itself been demonstrated to participate in nociception prior to this time. We set out to test the hypothesis that spinal CK2 regulates nociception using several pain models. Our first studies focused on the ability of the selective CK2 inhibitors 4,5,6,7-tetrabromobenzotriazole (TBBT) and 5,6-dichloro-1-β- d-ribofuranosylbenzimidazole (DRB) to reduce formalin-stimulated pain behaviors in mice. Both phases of the response to subcutaneous formalin were strongly inhibited by intrathecal administration of TBBT or DRB in dose-dependent fashion. Likewise, using the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, TBBT was observed to strongly reduce mechanical allodynia. The inhibition of spinal CK2 with either inhibitor did not, however, alter withdrawal latencies in the hotplate thermal pain model while intrathecal morphine was very effective. Immunohistochemical studies demonstrated all three known CK2 subunits, α, α′ and β to be expressed in spinal cord tissue as did real-time PCR experiments. While mRNA levels for each of the subunits was transiently enhanced after formalin or CFA hindpaw injection, overall spinal cord protein levels were not elevated in a sustained fashion. Our results indicate that CK2 participates in inflammatory nociception both in the acute and chronic phases. Simple changes in the abundance of spinal CK2 subunits do not likely underlie these phenomena, however.

Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture

Gerard W. Ostheimer “What’s New in Obstetric Anesthesia” Lecture

Antinociceptive effects of choline against acute and inflammatory pain

We used the hot plate test and the formalin test to evaluate the antinociception of choline after i.c.v. or i.v. administration. The analgesic mechanism of choline was also studied. The response latency of mice was significantly prolonged in the hot plate test after choline (90–120 μg/animals) i.c.v. administration in a dose-dependent manner. Pretreatment with methyllycaconitine citrate (MLA), α-bungarotoxin, or atropine blocked the antinociception of choline in the hot plate test. In contrast, mecamylamine and naloxone had no effect. No antinociceptive action of choline was found in the hot plate test, but it did have an effect in the late phase of the formalin test after i.v. administration. The effect of choline on anti-inflammatory pain was blocked by MLA, but not by mecamylamine, naloxone and atropine, which is indicative of the involvement of α7 receptors in peripheral sites. When choline (2 mg/kg) was coadministered with aspirin (9.4 mg/kg), the licking/biting times in the late phase significantly decreased, although no effects were shown when these doses of drugs were used alone. Similarly, coadministration of choline (2 mg/kg) with morphine (0.165 mg/kg) significantly increased the antinociception of morphine in the late phase, but had no effect in the early phase. These results demonstrate that activation of α7 nicotinic receptors by choline elicits antinociceptive effects both in an acute thermal pain model and in an inflammatory pain model. Choline holds promise for development as a non-addictive analgesic drug and in reducing the regular dose of aspirin or morphine in inflammatory pain.

Antinociceptive Properties of Mixture of α-Amyrin and β-Amyrin Triterpenes: Evidence for Participation of Protein Kinase C and Protein Kinase A Pathways

The mixture of the two pentacyclic triterpenes alpha-amyrin and beta-amyrin, isolated from the resin of Protium kleinii and given by intraperitoneal (i.p.) or oral (p.o.) routes, caused dose-related and significant antinociception against the visceral pain in mice produced by i.p. injection of acetic acid. Moreover, i.p., p.o., intracerebroventricular (i.c.v.), or intrathecal (i.t.) administration of alpha,beta-amyrin inhibited both neurogenic and inflammatory phases of the overt nociception caused by intraplantar (i.pl.) injection of formalin. Likewise, alpha,beta-amyrin given by i.p., p.o., i.t., or i.c.v. routes inhibits the neurogenic nociception induced by capsaicin. Moreover, i.p. treatment with alpha,beta-amyrin was able to reduce the nociception produced by 8-bromo-cAMP (8-Br-cAMP) and by 12-O-tetradecanoylphorbol-13-acetate (TPA) or the hyperalgesia caused by glutamate. On the other hand, in contrast to morphine, alpha,beta-amyrin failed to cause analgesia in thermal models of pain. The antinociception caused by the mixture of compounds seems to involve mechanisms independent of opioid, alpha-adrenergic, serotoninergic, and nitrergic system mediation, since it was not affected by naloxone, prazosin, yohimbine, DL-p-chlorophenylalanine methyl ester, or L-arginine. Interestingly, the i.p. administration of alpha,beta-amyrin reduced the mechanical hyperalgesia produced by i.pl. injection of carrageenan, capsaicin, bradykinin, substance P, prostaglandin E2, 8-Br-cAMP, and TPA in rats. However, the mixture of compounds failed to alter the binding sites of [3H]bradykinin, [3H]resiniferatoxin, or [3H]glutamate in vitro. It is concluded that the mixture of triterpene alpha-amyrin and beta-amyrin produced consistent peripheral, spinal, and supraspinal antinociception in rodents, especially when assessed in inflammatory models of pain. The mechanisms involved in their action are not completely understood but seem to involve the inhibition of protein kinase A- and protein kinase C-sensitive pathways.

Antinociceptive profile of (-)-spectaline: a piperidine alkaloid from Cassia leptophylla.

The antinociceptive activity of (-)-spectaline (1), a piperidine alkaloid isolated from Cassia leptophylla Vog. (Leguminosae), was investigated. We have also studied the acute oral toxicity of 1 in mice and it did not show any signals of toxicity in doses lower than 400 micromol/kg. The antinociceptive effect of 1 was evaluated on chemical (acetic acid, formalin and capsaicin) and thermal (hot plate and tail flick) pain models in mice, using classical standard drugs. Dipyrone ID (50) = 14.68 micromol/kg (4.8 mg/kg), indomethacin ID (50) = 0.78 micromol/kg (0.28 mg/kg) and (-)-spectaline ID (50) = 48.49 micromol/kg (15.75 mg/kg), all produced a significant inhibition of acetic acid-induced abdominal writhing in mice. (-)-Spectaline was inactive in the hyperalgesic model of formalin and did not show any central analgesic activity (hot plate and tail flick models). In the capsaicin-induced neurogenic pain model, (-)-spectaline presented an important inhibitory effect with an ID (50) = 20.81 microg/paw and dipyrone ID (50) = 19.89 microg/paw. The ensemble of results permitted us to identify 1 as an antinociceptive compound. The mechanism underlying this antinociceptive effect of 1 remains unknown, but the results suggest that such an effect could be related to pathways associated to vanilloid receptor systems.

L’administration intradermique de sufentanil n’améliore pas l’anesthésie locale induite par la lidocaïne

Peripheral opioid receptors may result in antinociceptive effects when occupied by opioids. This study examined intradermally injected sufentanil (S), a highly lipid soluble opioid, administered with and without lidocaine (L), in a thermal pain model. Nine volunteers were instructed on the method of magnitude estimation of pain before undergoing baseline testing with seven seconds thermal stimuli between 44 and 52 degrees C, delivered by a contact thermal stimulator at five cutaneous forearm sites. Then, four sites randomly received injections of equal volumes (0.1 mL) of either normal saline (NS), lidocaine 0.5% (L), sufentanil 0.75 microg (S), lidocaine 0.5% plus sufentanil 0.75 microg (L+S), and one site was not injected and served as reference (REF). Testing was repeated at six, 30, 60, 90, 120, and 150 min following injection. The pain elicited by each stimulus was normalized to the subject's response to the 50 degrees C stimulus at the REF site. Baseline testing showed small (P = ns) differences in pain scores. At six minutes, the lidocaine sites (L, L+S) had pain scores that were mean 83% (range 78-88%) lower than the other sites (P < 0.05), but there was no difference between the L and L+S sites or between the S and NS or REF sites. At 30 and 60 min these pain scores were mean 38% (29-44%) and 20% (8-30%) less than at the REF, NS, and S sites (P = ns). At 90 min and later times, the pain scores had returned to baseline. These results suggest that intradermal sufentanil alone has no analgesic effect. Further, in combination with lidocaine, sufentanil does neither potentiate nor prolong the analgesic effect of lidocaine.

Isobolographic analysis of the analgesic interactions between ketamine and tramadol.

Owing to different mechanisms of analgesia, we hypothesized that the combination of ketamine and tramadol could produce synergistic or additive antinociceptive effects. Swiss albino mice were administered intraperitoneally with ketamine, tramadol, a combination of ketamine and tramadol, or saline, and the resulting antinociceptive effects were tested in the mouse tail-flick and formalin tests. The potencies of the two drugs alone or in combination were obtained by fitting data to the Sigmoid Emax equation. Isobolographic analysis was performed to evaluate the interaction. CNS depression was also monitored. Results showed that tramadol exhibited apparent dose-dependent effects in the tail-flick test, and in phase 1 and phase 2 of the formalin test. Ketamine dose-dependently inhibited the phase 2 responses, but failed to modify the phase 1 and tail-flick responses. Combination of tramadol and ketamine produced significant synergistic interactions only in phase 2 of the formalin test (P < 0.05). The synergistic combinations also displayed less CNS depression than when an equianalgesic dose of ketamine was administered alone. We conclude that in the acute thermal or chemical pain model, ketamine is not effective and the net effect of ketamine and tramadol in combination was simply additive after systemic administration. However, the coadministration produced synergistic antinociception in the chemical-induced persistent pain model.

Adrenergic mechanisms in antinociceptive effects of non steroidal anti-inflammatory drugs in acute thermal nociception in mice.

The interactions of alpha-adrenoceptors with the antinociceptive effects of non-steroidal antiinflammatory drugs (NSAIDs) were assessed in acute thermal nociception in mice. The analgesic effect was analyzed by the tail-flick test. The pretreatment with yohimbine (1 mg/kg i.p.), 30 min prior to the intraperitoneal injection of ketoprofen (50 mg/kg), diclofenac (30 mg/kg) and piroxicam (50 mg/kg) antagonized the antinociception induced by these NSAIDs, significantly reducing the tail-flick latency. Yohimbine did not affect paracetamol (125 mg/kg) induced antinociception. Prazosin (1 mg/kg i.p.) antagonized only the effect of paracetamol, without affecting the latency of the other drugs. When NSAIDs were administered i.t. (ketoprofen 2 m/kg; diclofenac 0.9 mg/kg; piroxicam 1.5 mg/kg; paracetamol 3.75 mg/kg), the same results were obtained after i.p. pretreatment with yohimbine and prazosin. The pretreatment of phenoxybenzamine (1 mg/kg i.p.) antagonized all antinociceptive effects. NSAIDs induced antinociception in an acute thermal pain model without inflammation. The mechanism of antinociception induced by ketoprofen, diclofenac and piroxicam involves an activation of alpha2-adrenoceptors at spinal and supraspinal levels, while paracetamol-induced antinociception is probably due mainly to central activation of the descending noradrenergic inhibitory system by alpha1-adrenoceptors.

Nefopam reduces thermal hypersensitivity in acute and postoperative pain models in the rat

The activity of nefopam, a centrally acting compound, not structurally related to other analgesics, was examined in acute and postoperative thermal pain models in the rat. Its antinociceptive potency was evaluated using heat noxious stimuli either in intact or in injured animals after skin and muscular incisions. In the hot plate and in the plantar tests, nefopam after acute administration by different routes exhibited a dose-dependent attenuation of the nociceptive responses at 10–30 mg kg −1by intraperitoneal or subcutaneous administration, at 60 mg kg −1by oral dosing, and from 3 mg kg −1after intravenous injection. In the postoperative pain model, at 30 mg kg −1nefopam augmented the endpoint to thermal threshold, 60 and 90 minutes after administration compared to the threshold recorded after the incision. In the same conditions, morphine and tramadol displayed antinociceptive activities. As the plantar test provides a good index of nociception in humans, these results point out the usefulness of nefopam for attenuating moderate to severe pain, and for postoperative analgesia. In conclusion, nefopam has shown potent properties to reduce thermal hypersensitivity after acute or postoperative pain in rats.

Evaluation of the antinociceptive action caused by ether fraction and a triterpene isolated from resin of Protium kleinii

This study investigates the antinociception caused by i.p. and p.o. administration of ether fraction and the triterpene identified as urs-12-ene-3β-16β-diol, known as Brein, isolated from Protium kleinii in several models of nociception in mice. The systemic administration of ether fraction (0.3 to 10 mg/kg, i.p. or 3 to 60 mg/kg, p.o.) caused a dose-related antinociception when assessed against acetic acid-induced writhing, with mean ID 50 values of 1.2 and 16.4 mg/kg, respectively. The ether fraction (5 to 60 mg/kg, i.p. or 30 to 300 mg/kg, p.o.) also produced dose-related inhibition of both phases of formalin induced licking. The mean ID 50s values for the early phase were > 60.0 and 62.1 mg/kg, while for the late phase they were 15.4 and 60.0 mg/kg, respectively, given by i.p. and p.o. routes. The ether fraction (3 to 30 mg/kg, i.p. or 10 to 100 mg/kg, p.o.) produced significant inhibition of the neurogenic nociception caused by topical injection of capsaicin, with mean ID 50 values of 6.2 and 16.0 mg/kg, respectively. Given orally (1 to 30 mg/kg) the ether fraction produced graded and pronounced inhibition of glutamate-induced hyperalgesia in mice with a mean ID 50 value of 15.2 mg/kg. In contrast, the ether fraction failed to produce antinociception when assessed in the thermal model of pain, the tail flick and hot plate tests. The antinociception caused by the ether fraction, in contrast to that of morphine, was not reversed by naloxone when assessed in the formalin-induced licking. The ether fraction did not affect motor coordination or the core body temperature in mices .The triterpene Brein isolated from P. kleinii, given by i.p. route (10 to 100 mg/kg) produced dose-related inhibition of both phases of formalin induced-licking, with mean ID 50s values of 15.3 and 20.6 for the early and the late phases, respectively. These data show that the active principle(s) present in the ether fraction from the resin of P. kleinii elicited pronounced antinociception when assessed by i.p. or p.o routes, against both inflammatory and neurogenic nociception. Such effects seem, at least in part, to be related to the presence of the triterpene Brein in the extract. The mechanisms responsible for the antinociceptive action are at this moment not completely understood, but the involvement of the opioid pathway seems unlikely.