aconitine and Pain

Patients suffering from cancer induced bone pain (CIBP) have a poor quality of life that is exacerbated by the lack of effective therapeutic drugs. Monkshood is a flowering plant that has been used in traditional Chinese medicine where it has been used to relieve cold pain. Aconitine is the active component of monkshood, but the molecular mechanism for how this compound reduces pain is unclear.. In this study, we employed molecular and behavioral experiments to explore the analgesic effect of aconitine. We observed aconitine alleviated cold hyperalgesia and AITC (allyl-isothiocyanate, TRPA1 agonist) induced pain. Interestingly, we found aconitine directly inhibits TRPA1 activity in calcium imaging studies. More importantly, we found aconitine alleviated cold and mechanical allodynia in CIBP mice. Both the activity and expression of TRPA1 in L4 and L5 DRG (Dorsal Root Ganglion) neurons were reduced with the treatment of aconitine in the CIBP model. Moreover, we observed aconiti radix (AR) and aconiti kusnezoffii radix (AKR), both components of monkshood that contain aconitine, alleviated cold hyperalgesia and AITC induced pain. Furthermore, both AR and AKR alleviated CIBP induced cold allodynia and mechanical allodynia.. Taken together, aconitine alleviates both cold and mechanical allodynia in cancer induced bone pain via the regulation of TRPA1. This research on the analgesic effect of aconitine in cancer induced bone pain highlights a component of a traditional Chinese medicine may have clinical applications for pain.

Topics: Aconitine; Analgesics; Animals; Cancer Pain; Hyperalgesia; Mice; Neoplasms; Pain; Quality of Life; TRPA1 Cation Channel

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.

Topics: Acetic Acid; Aconitine; Analgesics; Animals; Aspirin; Disease Models, Animal; Edema; Female; Formaldehyde; Freund's Adjuvant; Hot Temperature; Mice; Mice, Inbred C57BL; Pain; Pain Threshold

Topics: Aconitine; Analgesics; Animals; Male; Mice; Nociception; ortho-Aminobenzoates; Pain; Pyrimidines

Aconitine and its structurally-related diterpenoid alkaloids have been shown to interact differentially with neuronal voltage-dependent sodium channels, which was suggested to be responsible for their analgesia and toxicity. Bulleyaconitine A (BAA) is an aconitine analogue and has been prescribed for the management of pain. The present study aimed to evaluate the inhibitory effects of BAA on pain hypersensitivity and morphine antinociceptive tolerance, and explore whether the expression of dynorphin A in spinal microglia was responsible for its actions. Single intrathecal or subcutaneous (but not intraventricular or local) injection of BAA blocked spinal nerve ligation-induced painful neuropathy, bone cancer-induced pain, and formalin-induced tonic pain by 60 to 100% with the median effective dose values of 94 to 126 ng per rat (intrathecal) and 42 to 59 μg/kg (subcutaneous), respectively. After chronic treatment, BAA did not induce either self-tolerance to antinociception or cross-tolerance to morphine antinociception, and completely inhibited morphine tolerance. The microglial inhibitor minocycline entirely blocked spinal BAA (but not exogenous dynorphin A) antinociception, but failed to attenuate spinal BAA neurotoxicity. In a minocycline-sensitive and lidocaine- or ropivacaine-insensitive manner, BAA stimulated the expression of dynorphin A in the spinal cord, and primary cultures of microglia but not of neurons or astrocytes. The blockade effects of BAA on nociception and morphine tolerance were totally eliminated by the specific dynorphin A antiserum and/or κ-opioid receptor antagonist. Our results suggest that BAA eliminates pain hypersensitivity and morphine tolerance through directly stimulating dynorphin A expression in spinal microglia, which is not dependent on the interactions with sodium channels.. The newly illustrated mechanisms underlying BAA antinociception help us to better understand and develop novel dynorphin A expression-based painkillers to treat chronic pain.

Topics: Aconitine; Aconitum; Analgesics; Analysis of Variance; Animals; Animals, Newborn; Bone Neoplasms; CD11b Antigen; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Dynorphins; Female; Functional Laterality; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Microglia; Microscopy, Confocal; Morphine; Neurons; Pain; Pain Measurement; Phosphopyruvate Hydratase; Rats; Receptors, Opioid, kappa; RNA, Messenger; Spinal Cord; Time Factors

We compared analgesic activities of individual alkaloids extracted from Baikal aconite (Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation.

Topics: Acetic Acid; Aconitine; Aconitum; Alkaloids; Analgesics; Animals; Animals, Outbred Strains; Arthritis, Experimental; Dipyrone; Freund's Adjuvant; Injections, Intraperitoneal; Mice; Pain; Plant Extracts; Rats; Seizures; Vocalization, Animal

Four new C18-diterpenoid alkaloids, weisaconitines A-D (1-4), were isolated from Aconitum weixiense. Based on extensive UV, IR, MS, 1D and 2D NMR analyses, their structures were elucidated as 8-O-ethyldolaconine (1), 4-demethylgenicunine B (2), 14-oxoaconosine (3), and 8-O-ethylaconosine (4). The analgesic activity of compound 4 was studied with CH3COOH-induced writhing model in mice. Compound 4 showed writhing inhibitions of 24% (50 mg/kg), 26% (100 mg/kg) and 34% (200 mg/kg), respectively, as compared to the reference drug aspirin (63%) at a dose of 200 mg/kg.

Topics: Acetic Acid; Aconitine; Aconitum; Analgesics; Animals; Drugs, Chinese Herbal; Mice; Mice, Inbred Strains; Molecular Structure; Pain; Phytotherapy

To investigate the analgesic effect of cobratoxin (CTX), a long-chain α-neurotoxin from Thailand cobra venom, in a rat model of formalin-induced inflammatory pain.. Inflammatory pain was induced in SD rats via injecting 5% formalin (50 μL) into the plantar surface of their right hind paw. CTX and other agents were ip administered before formalin injection. The time that the animals spent for licking the injected paw was counted every 5 min for 1 h.. CTX (25, 34, and 45 μg/kg) exhibited a dose-dependent analgesic effect during the phase 1 (0-15 min) and phase 2 (20-60 min) response induced by formalin. Pretreatment with naloxone (0.5 or 2.5 mg/kg) did not block the analgesic effect of CTX. Pretreatment with atropine at 5 mg/kg, but not at 2.5 mg/kg, antagonized the analgesic effect of CTX. Treatment with the nonselective nAChR antagonist mecamylamine (3 mg/kg) inhibited the analgesic effects of CTX in Phase 1 and Phase 2 responses, while with the selective α7-nAChR antagonist methyllycaconitine (3 mg/kg) antagonized the effect of CTX only in the Phase 1 response. Treatment with the α7-nAChR agonist PNU282987 (3 mg/kg) significantly reduced the formalin-induced phase 2 pain response, but only slightly reduced the Phase 1 pain response.. The results suggest that CTX exerts an antinociceptive effect in formalin-induced inflammatory pain, which appears to be mediated by mAChR and α7-nAChR.

Topics: Aconitine; Adjuvants, Anesthesia; Analgesics; Animals; Antihypertensive Agents; Atropine; Cobra Neurotoxin Proteins; Drug Interactions; Formaldehyde; Male; Mecamylamine; Naloxone; Narcotic Antagonists; Nicotinic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Receptors, Cholinergic

CDP-choline (citicholine; cytidine-5'-diphosphate choline) is an endogenously produced nucleotide which, when injected intracerebroventricularly, exerts an antinociceptive effect in acute pain models mediated by central cholinergic mechanisms and alpha7 nicotinic acetylcholine receptors (alpha7nAChR). Previous reports also suggest that the peripheral cholinergic system has an antiinflammatory role mediated by alpha7nAChRs on macrophages.. We used male Sprague-Dawley rats to assess the antihypersensitivity and antiinflammatory effect of CDP-choline after intraplantar injection of carrageenan (100 microL, 2%). Mechanical paw withdrawal thresholds and paw thickness were measured by Randall-Selitto testing and microcallipers, respectively. All drugs were administered intraplantarly in a volume 50 microL.. CDP-choline (1, 2.5, 5 micromol; intraplantar) increased the mechanical paw withdrawal threshold and decreased paw edema in a dose- and time-dependent manner in the carrageenan-injected hindpaw. CDP-choline administration to the noninflamed contralateral hindpaw did not alter ipsilateral inflammation. Methyllycaconitine (100 nmol), a selective alpha7nAChR antagonist, completely blocked the effects of CDP-choline when administered to the inflamed hindpaw. However, the administration of methyllycaconitine to the contralateral hindpaw did not block the effects of CDP-choline in the ipsilateral paw. The administration of CDP-choline (5 micromol) 10 min after carrageenan administration to the ipsilateral hindpaw did not reduce swelling and edema but did significantly reduce hypersensitivity. Treatment with CDP-choline decreased tumor necrosis factor-alpha production in the rat paw tissue after carrageenan.. The results of this study suggest that intraplantar CDP-choline has antihypersensitivity and antiinflammatory effects mediated via alpha7nAChRs in the carrageenan-induced inflammatory pain model.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Anti-Inflammatory Agents; Carrageenan; Cytidine Diphosphate Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Inflammation; Injections; Male; Nicotinic Agonists; Nicotinic Antagonists; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Time Factors; Tumor Necrosis Factor-alpha

To explore the analgesic and anti-inflammatory effects of lappaconitine gelata (LA).. The writhing response induced by acetic acid, the pain response induced by formaldehyde and hot plate method in the mouse, and the paw edema induced by egg albumen in the rat and the ear edema induced by xylene in the mouse were used for investigation on the analgesic and anti-inflammatory effects of LA.. The writhing response induced by acetic acid, the pain response induced by formaldehyde and hot plate methods was significantly inhibited by LA. In addition, the paw edema induced by egg albumen in the rat and the ear edema induced by xylene in the mouse were all significantly suppressed by LA.. LA has the analgesic and anti-inflammatory effects.

Topics: Aconitine; Analgesics; Animals; Anti-Inflammatory Agents; Drugs, Chinese Herbal; Edema; Mice; Pain; Rats; Rats, Wistar

The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not been fully elucidated because of the lack, until recently, of selective tool compounds. (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective for the alpha(7)nAChR and in the present study was found to be efficacious in inflammatory pain models in 2 species. Compound B reversed complete Freund adjuvant-induced reductions in paw withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum reversals of 65% +/- 4% at 10 mg/kg and 87% +/- 15% at 20 mg/kg. When rats and mice were predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals of only 11% +/- 5% at 10 mg/kg and 5% +/- 13% at 20 mg/kg, confirming activity via nicotinic receptors. Rats were also predosed systemically with the selective low-brain penetrant alpha(7)-antagonist methyllycaconitine, which had no effect on agonist activity (90% +/- 18% at 10 mg/kg), suggesting a central involvement. This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% +/- 7%).. These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the alpha(7)-nicotinic receptor for the treatment of inflammatory pain.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Behavior, Animal; Benzofurans; Dose-Response Relationship, Drug; Female; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Intraperitoneal; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Models, Animal; Nicotinic Antagonists; Pain; Pain Measurement; Quinuclidines; Rats; Receptors, Nicotinic; Weight-Bearing

Processed Aconiti tuber (PAT) is a herbal medicine that has been widely used as an analgesic since ancient times. We investigated effects of subanalgesic doses of PAT on morphine tolerance in mice. Mice received subcutaneous morphine (10 mg/kg) and oral PAT at subanalgesic doses (0.1 or 0.3 g/kg), once a day for 7 days. Mechanical nociceptive thresholds were measured using the tail pressure test, at 60 min after the daily s.c. morphine injections. In the placebo-treated group, repeated administration of s.c. morphine resulted in development of analgesic tolerance. In the PAT-treated groups, oral PAT attenuated morphine tolerance, dose-dependently. The main ingredient alkaloid of PAT causing its tolerance-attenuating activity was mesaconitine, but other ingredient alkaloids, such as aconitine and hypaconitine, also contributed to this activity. In addition, repeated treatment with PAT could reverse already-developed morphine tolerance. Subanalgesic doses of oral PAT thus can attenuate and reverse morphine tolerance in mice.

Topics: Aconitine; Aconitum; Alkaloids; Analgesics; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Drugs, Chinese Herbal; Male; Mice; Morphine; Pain; Pain Measurement; Pain Threshold; Plant Tubers; Time Factors

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 mug/animals) i.c.v. administration in a dose-dependent manner. Pretreatment with methyllycaconitine citrate (MLA), alpha-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 alpha7 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 alpha7 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.

Topics: Aconitine; Acute Disease; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Anti-Inflammatory Agents; Aspirin; Atropine; Bungarotoxins; Central Nervous System; Choline; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Inflammation; Mice; Morphine; Muscarinic Antagonists; Nicotinic Antagonists; Nociceptors; Pain; Pain Measurement; Reaction Time; Receptors, Nicotinic

A recent model of acute incisional pain has been characterized that strongly parallels the postoperative period in patients experiencing evoked pain. In that setting, abundant literature has revealed antihypersensitive effects produced by intrathecally administered alpha2-adrenergic receptor agonists, such as clonidine, in both animals and humans. Recent reports have suggested an obligatory role of spinal acetylcholine receptors in the analgesic action of intrathecal clonidine. The authors sought to determine the involvement of spinal muscarinic and nicotinic receptor subpopulations in the antihypersensitivity effect of intrathecal clonidine in a rodent model for human postoperative pain.. After intrathecal catheterization, rats underwent superficial plantar incision. Clonidine or a combination of clonidine and muscarinic receptor subtype antagonists (M1, M2, M3, and M4) or nicotinic receptor subtype antagonists (alpha4beta2 and alpha7) were intrathecally administered, and withdrawal thresholds to mechanical stimuli were examined.. Spinal clonidine maximally reduced hypersensitivity adjacent to the wound 30 min after its injection. When animals were intrathecally pretreated with the M1 muscarinic antagonist toxin MT-7, the M3 muscarinic antagonist 4-diphenylacetoxy-N-methylpiperidine, and the M4 muscarinic antagonist toxin MT-3, clonidine lost its antihypersensitive action. When animals were intrathecally pretreated with the alpha4beta2 nicotinic receptor antagonist dihydro-beta-erythroidine, but not with the alpha7 nicotinic receptor antagonist methyllycaconitine, the antihypersensitivity action of clonidine was abolished.. These data indicate for the first time that the clonidine-induced increase in punctuate mechanical threshold is mediated via the activation of all but M2 muscarinic receptor subtypes, and via the activation of alpha4beta2 but not alpha7 nicotinic receptor subtypes in a rodent model for human postoperative pain.

Topics: Aconitine; Adrenergic alpha-Agonists; Animals; Behavior, Animal; Clonidine; Diamines; Dihydro-beta-Erythroidine; Injections, Spinal; Male; Muscarinic Agonists; Nicotinic Agonists; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptors, Muscarinic; Receptors, Nicotinic; Spine

Thin layer chromatography was performed to identify the ingredients of Effervescent Granules for arresting cold pain (Hantongding Paoteng Chongji). The limited doses of aconitine, granularity, moisture, acidity, sugar content, etc. were detected, and the contents of paeoniflorin, glycyrrhetinic acid and total alkaloids were determined. Thus, the quality standards for pharmaceutical preparation were preliminarily worked out.

Topics: Aconitine; Alkaloids; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Chromatography, Thin Layer; Drug Combinations; Drugs, Chinese Herbal; Glucosides; Glycyrrhetinic Acid; Humans; Monoterpenes; Pain; Particle Size; Quality Control

3, 15-Diacetylbenzoylaconine (Dia) is a new aconite alkaloid derivative. The analgesic ED50 (95% confidence limit) of sc Dia measured with the HAc-induced writhing method, hot-plate method and electric stimulation method in mice were 2.76 (2.34-3.26), 3.50 (2.69-4.54), and 4.20 (3.72-4.73) mg.kg-1, respectively. With the hot-plate method and tail flick method in rats, the analgesic ED50 of ip Dia were 2.75 (2.28-3.31) and 5.24 (4.35-6.31) mg.kg-1, respectively. The LD50 of sc Dia in mice and ip Dia in rats were 21.68 (17.25-27.25) and 10.96 (8.24-14.56) mg.kg-1, respectively. The magnitude of the analgesic therapeutic indices of Dia, 3-acetylaconitine (Ace) and aconitine (Aco) in all the above-mentioned algo-model were in the order of Dia > Ace > Aco. When they were injected iv at 0.1 ml.min-1 in rats, the doses of Dia, Ace, and Aco producing arrythmia were 3.3, 0.8, and 0.5 times as large as those producing analgesia while those of Dia, Ace, and Aco inducing respiratory inhibition were 3.9, 0.5 and 0.3 times, respectively. The magnitudes of the oil/water distribution coefficients with two method and the quotient ED50 icv/ED50 sc of Dia and Ace were > Aco.

Topics: Aconitine; Alkaloids; Analgesics; Animals; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Female; Lethal Dose 50; Male; Mice; Pain; Pain Threshold; Rats; Rats, Wistar; Respiration

The anti-nociceptive effect of processed aconiti tuber (TJ-3021), one of the traditional oriental herbal medicines (Kampo), was investigated by utilizing various methods including repeated cold stress and adjuvant articular inflammation in rats and mice. Analgesic potency was compared with that of mesaconitine, a potent component of aconitine alkaloids, and other analgesic agents. It was found that mesaconitine was more potent than morphine, and a processed aconiti tuber [(TJ-3021), Tsumura-shuchi-bushi-matsu] showed some analgesic effect, although it was weaker than those of dichlofenac, aminopyrine and indomethacine.

Topics: Acetates; Acetic Acid; Aconitine; Analgesics; Animals; Arthritis, Experimental; Cold Temperature; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Male; Mice; Mice, Inbred ICR; Pain; Pain Threshold; Rats; Rats, Sprague-Dawley

We explored the possible role of the specific regions in the brain stem on the antinociceptive actions of mesaconitine (MA) and benzoylmesaconine (BM) by the microinjection of MA and BM into nucleus reticularis paragigantocellularis (NRPG), nucleus raphe magnus (NRM), and periaqueductal gray (PAG). MA microinjected into NRPG, NRM, or PAG elicited a dose-dependent antinociceptive action, whereas BM injected into NRM or PAG elicited a dose-dependent antinociceptive action but not in NRPG. The NRM appeared to be the most sensitive region among the three tested locations.

Topics: Aconitine; Analgesics; Analysis of Variance; Animals; Brain; Male; Microinjections; Models, Neurological; Organ Specificity; Pain; Periaqueductal Gray; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Reticular Formation

In the rat hot plate test, vocalization induced by electric stimulation, tail flick test, and the mouse acetic acid writhing test, 3, 15-diacetylbenzoylaconine (DABA) ip exhibited a dose-dependent analgesic activity. Intrathecally (ith) administered DABA (527, 1186 micrograms.kg-1) had no analgesic action. Microinjection of DABA 35-75 micrograms.kg-1 or 20 micrograms into the cerebral ventricle (icv) or the periaqueductal gray (PAG) exerted a remarkable analgesic activity, which was abolished after bilateral lesions of locus coeruleus (LC). Microinjection of DABA (20 micrograms) into LC failed to produce apparent analgesic action. These results suggested that the sites of analgesia of DABA were mainly at the central supraspinal structures, and PAG was one of the primary sites, while LC was one of the intermediate links.

Topics: Aconitine; Alkaloids; Analgesics; Animals; Female; Injections, Intraventricular; Injections, Spinal; Locus Coeruleus; Male; Mice; Pain; Pain Threshold; Periaqueductal Gray; Rats; Rats, Wistar

The effects of lappaconitine (LA) and N-deacetyllappaconitine (DLA) on footshock-induced analgesia (FSIA) were studied by the rat tail flick test. Rats subjected to 90 s nonescaping footshock had a significant increase in tail flick latency. Naloxone (4 micrograms, i.c.v.) partially antagonized the FSIA. After 5 consecutive exposures to footshock, rats developed a complete tolerance to the FSIA. The rats tolerant to FSIA showed a cross-tolerance to morphine- but not LA- and DLA-induced analgesia. Administrations of subanalgesic doses of LA and DLA potentiated the FSIA in both intact and adrenalectomized rats.

Topics: Aconitine; Adrenalectomy; Analgesics; Animals; Drug Synergism; Drug Tolerance; Naloxone; Pain; Rats; Rats, Inbred Strains

In the rat tail flick test, ip LA 6 mg/kg, icv DLA 60 micrograms and icv or with morphine 5 micrograms exhibited significant analgesia. But with either LA 40 micrograms or DLA 60 micrograms was inactive. Naloxone (4 micrograms icv) which antagonized morphine analgesia failed to alter the analgesia induced by LA and DLA. Microinjection of DLA 20 micrograms or morphine 5 micrograms into the periaqueductal gray (PAG) or nucleus raphe magnus (NRM) produced markedly analgesic activity. The effects of electrolytic and kainic acid (0.8 micrograms) lesions of the PAG and NRM on the analgesia elicited in the rat from ip LA, icv DLA and morphine were also evaluated. No change in baseline tail flick latency was observed following lesions of the PAG and NRM. But lesions of the PAG and NRM significantly attenuated the analgesia mediated by LA, DLA and morphine. These results suggest that supraspinal sites, especially the PAG and NRM, are involved in the analgesic action induced by LA, DLA and morphine.

Topics: Aconitine; Analgesia; Animals; Male; Morphine; Pain; Periaqueductal Gray; Raphe Nuclei; Rats; Sensory Thresholds

In the rat tail-flick test it was shown that ip lappaconitine (LA) 1-6 mg/kg, N-deacetyllappaconitine (DLA) 4-10 mg/kg or icv DLA 20-60 micrograms/rat exhibited a dose-dependent analgesic activity, but icv LA 20-40 micrograms/rat was inactive. The analgesic potency of ip LA was a little more potent than that of DLA and slightly weaker than that of morphine (P less than 0.05). Combined ip of subanalgesic doses of morphine and LA or DLA produced significant analgesic action. Analgesia mediated by LA was not antagonized by naloxone. The analgesic effect induced by LA or DLA was abolished and restored 3 and 120 h, respectively, after ip reserpine 3 mg/kg. Concomitant administration of 1-tryptophan or 5-HT as well as premedication of alpha-methyldopa prevented reserpine-induced decrease on LA or DLA analgesia. The elevation of brain 5-HT level by icv 5-HT significantly enhanced the analgesia of LA and DLA. LA- or DLA-induced analgesia was attenuated by pretreatment of p-chlorophenylalanine but this attenuation was reversed by icv 5-HT. p-Chloroamphetamine also markedly reduced LA- or DLA-induced analgesia. It is concluded that the central serotoninergic system is involved in the modulation of LA- or DLA-induced analgesia.

Topics: Aconitine; Aconitum; Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Male; Morphine; Pain; Rats; Reserpine; Sensory Thresholds; Serotonin

The analgesic activity of lappaconitine, which is contained in the root of Aconitum sinomantanum Nakai, was examined after oral and subcutaneous administration to mice or rats by using methods for screening of analgesics, i.e., hot plate, tail immersion, tail pinch, tail pressure, acetic acid-induced writhing, bradykinin-induced flexor reflex of hind limb and Randall-Selitto methods. The results were compared with those for morphine, indometacin and acetylsalicylic acid (ASA). Analgesic activities of lappaconitine were greater than those of indometacin and ASA, but generally about 2 to 5 times less than those of morphine. However, in the rat tail immersion test, orally administered lappaconitine exhibited more potent analgesic activity than morphine; in this test, lappaconitine was almost equipotent when given orally and subcutaneously, whereas the potency of orally administered morphine was only one-twentieth of that of subcutaneously administered morphine. Like morphine, lappaconitine increased the pain threshold of the normal paw as well as that of the inflamed paw when tested by the Randall-Selitto method. The results show that lappaconitine has strong analgesic activity, and further suggest that the central nervous system may be involved in the action on the pain threshold.

Topics: Aconitine; Aconitum; Analgesics; Animals; Aspirin; Dose-Response Relationship, Drug; Hot Temperature; Indomethacin; Male; Mice; Morphine; Pain; Pressure; Rats; Rats, Inbred Strains; Reaction Time; Reflex

Topics: Aconitine; Aconitum; Analgesics; Animals; Female; Injections, Intraventricular; Injections, Spinal; Locus Coeruleus; Male; Naloxone; Norepinephrine; Pain; Phenoxybenzamine; Rats; Reserpine; Sensory Thresholds

Topics: Aconitine; Aconitum; Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Macaca mulatta; Male; Mice; Pain; Rats; Sensory Thresholds; Substance-Related Disorders

Topics: Aconitine; Aconitum; Analgesics; Animals; Drug Tolerance; Female; Male; Mice; Naloxone; Pain; Rats; Reserpine; Sensory Thresholds; Serotonin; Substance-Related Disorders

A painful writhing syndrome is produced by aconitine when given intraperitoneally. It is similar to that induced by other chemical agent viz. phenylquinone, acetic acid, and bradykinin. Aconitine writhing is quick to appear, shows greater frequency and longer duration than that induced by other agents. The nonnarcotic analgesics more selectively antagonize the aconitine writhing than orally-administered narcotic analgesics. Thus the aconitine writhing method is a very suitable method for the selective screening of the aspirin type of analgesic agent.

Topics: Aconitine; Aconitum; Analgesics; Animals; Aspirin; Behavior, Animal; Caffeine; Drug Evaluation, Preclinical; Mephenesin; Mice; Narcotics; Pain