Pharmacological studies of lappaconitine. Analgesia produced by intracerebroventricular, intracisternal and intrathecal injections.

Ono, Mamoru; Satoh, Tetsuo

doi:10.1248/bpb1978.13.374

Cited by 20 publications

(8 citation statements)

References 8 publications

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“…Since naloxone failed to antagonize the 3-acetylaconitine-dependent antinociceptive action, the authors excluded an interaction with opioid receptors (Dang et al 1986). Similar results have been reported by Ono and Satoh (1990), who have demonstrated that naloxone does not affect the antinociceptive properties of lappaconitine. However, the mode of the antinociceptive action remains unsolved.…”

Section: Introductionsupporting

confidence: 91%

“…The most striking difference to these alkaloids is an inhibition of Na + channels by lappaconitine, as deduced from the suppression of aconitine-induced increase in [Ca 2+ ] i and the increase of excitation threshold observed in guinea-pig left atria. The antinociceptive properties of lappaconitine, previously shown with analgesic models like the tail pinch, hot plate and acetic acidinduced writhing assays (Ono and Satoh 1990), might therefore be explained by a mode of action similar to local anaesthetics. However, because of its lipophilic nature, an integration of lappaconitine into the cellular membrane as primary target cannot be ruled out, but seems to be unlikely since the K i value (11.5 µM) is rather low.…”

Section: Discussionmentioning

confidence: 81%

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Mode of antinociceptive and toxic action of alkaloids of Aconitum spec.

Gutser

Friese

Heubach

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Extracts of the plant Aconitum spec. are used in traditional Chinese medicine predominantly as anti-inflammatory and analgesic agents, the latter allegedly equally potent as morphine but without any habit-forming potential. As the only pharmacologically active compounds, the C19 diterpenoid alkaloid aconitine, and some of its derivatives, have been proven to be antinociceptive in different analgesic assays, but the mode of action is unknown. To elucidate the mode of action, ten aconitine-like derivatives were investigated with respect to their affinity for voltage-dependent Na+ channels, the action on synaptosomal Na+ and Ca2+ homoeostasis and their antinociceptive, arrhythmogenic and acute toxic properties. Since aconitine is known to bind to site II of Na+ channels, we determined the affinity of the aconitine-like derivatives in vitro to synaptosomal membranes by the [3H]-batrachotoxinin-binding assay and their properties on intrasynaptosomal concentrations of free Na+ and Ca2+ ([Na+]i and [Ca2+]i), both the latter determined fluorometrically with SBFI and Fura-2 respectively. Furthermore, the alkaloids' arrhythmogenic potential was investigated in guinea-pig isolated atria and the antinociceptive action on formalin-induced hyperalgesia and the acute toxic action estimated in mice. The results show that the alkaloids could be divided into at least three groups. The first is characterized by a high affinity to the site II of Na+ channels (Ki about 1.2 microM), the ability to enhance [Na+]i and [Ca2+]i (EC50 about 3 microM), a strong arrhythmogenic action that starts at about 30 nM, an antinociceptive effect (ED50 about 0.06 mg/kg) and high acute toxicity (LD50 values about 0.15 mg/kg). To this group belong aconitine, 3-acetylaconitine and hypaconitine. The second group, with lappaconitine as the only member, has an affinity to Na+ channels an order of magnitude lower (Ki = 11.5 microM), less acute toxicity (LD50 about 5 mg/kg), and a two orders of magnitude lower antinociceptive action (ED50 about 2.8 mg/kg) and lower cardiotoxicity (bradycardia observed at 3 microM). Additionally, lappaconitine suppresses the increase in [Ca2+]i of aconitine-stimulated synaptosomes and increases the excitation threshold of left atria, indicating an inhibition of Na+ channels. The other derivatives, i.e. delcorine, desoxydelcorine, karakoline, lappaconidine, lappaconine and lycoctonine, belong to the third group, which has hardly any effects. They have a low affinity to Na+ channels with Ki values in the millimolar range, show no effect on synaptosomal [Na+]i and [Ca2+]i, no arrhythmogenic potential up to 100 microM, no antinociceptive activity and low toxicity with LD50 values greater than 50 mg/kg. For the investigated alkaloids we suggest two different antinociceptive-like modes of action. Aconitine, hypaconitine and 3-acetylaconitine may induce a block of neuronal conduction by a permanent cell depolarisation, whereas lappaconitine might act like local anaesthetics. However, because of the low LD50/ED30 quotients of 2-6, the...

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Section: Introductionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 81%

Mode of antinociceptive and toxic action of alkaloids of Aconitum spec.

Gutser

Friese

Heubach

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…and i.t. injection of LA produces dose-dependent antinociception (13); and LA may act supra spinally to inhibit the spinal nociceptive trans mission (3). In the present study, s.c. and i.c.v.-administered LA-induced antinocicep tion was markedly reduced after spinalization.…”

Section: Discussionsupporting

confidence: 47%

Pharmacological Studies on Lappaconitine: Possible Interaction with Endogenous Noradrenergic and Serotonergic Pathways to Induce Antinociception.

Ono¹,

Satoh

1992

Jpn.J.Pharmacol

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Systemic and intracerebroventricular (i.c.v.) injections of lappaconitine (LA) produced a dose-dependent inhibition of the response to thermal stimulation in sham-operated mice as assayed by the tail-immersion test. After spinal transection, the antinociceptive potencies of s.c. or i.c.v.-administered LA were markedly re duced. Antinociception induced by systemically administered LA was clearly reduced by pretreatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine through the i.c.v. and intrathecal (i.t.) routes. When LA was administered by 1. c.v. -injection, the LA-induced antinociception was reduced by pretreatment with timolol, a Q-adrenergic antagonist, and ketanserin, a 5-HT2 antagonist. Administration of LA by the i.t. route resulted in a significant antinociceptive activity, which was also reduced by pretreat ment with phenoxybenzamine, an a-adrenergic antagonist, and mianserin, a 5-HT1 antagonist. The results of these studies suggest that the central noradrenergic and serotonergic systems may be involved in the antinociception of systemically adminis tered LA, and these pathways are mediated by /9-adrenoceptors and 5-HT2 receptors in the brain and a-adrenoceptors and 5-HT, receptors in the spinal cord.In a previous paper, we demonstrated that lappaconitine (LA) had naloxone-resistant analgesic effects (1). Furthermore, we re ported that a supraspinal-spinal interaction was important for the production of the anti nociceptive action of systemically administered LA (2) and that LA acted at the supraspinal level to inhibit nociceptive transmission or to block the spinal action of nociceptive neuro transmitters via the descending pathways (3).It is well-known that the descending inhibi tory systems play an important role in pain modulation and analgesia, and central norad renergic and serotonergic pathways, particular ly bulbospinal pathways, may modulate the transmission in these systems (4, 5).The purpose of the present study was to ex amine the role of central noradrenergic and serotonergic systems in the antinociceptive ac tion of LA. MATERIALS AND METHODS AnimalsMale mice of the Std:ddY strain, weighing 20 to 30 g, were used. Mice were maintained in a temperature and humidity-controlled room (22-23T, 50-60%) and allowed free access to food and water.

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“…When injected i.t., LA showed dose-depend ent antinociceptive activities against mecha nical, heat, and chemical nociception (18). Furthermore, we observed that systemically administered LA was distributed to the brain and the spinal cord, and the supraspinal-spinal interaction is important in antinociceptive ac tion (36).…”

Section: Discussionmentioning

confidence: 99%

“…), intracisternal, or i.t. injection, it produces dose-dependent anti nociception (18). The present study was per formed in order to investigate whether LA induced antinociception involves modulation of the SP and SOM neuronal systems in the brain and spinal cord.…”

mentioning

confidence: 99%

Pharmacological Studies on Lappaconitine: Antinociception and Inhibition of the Spinal Action of Substance P and Somatostatin.

Ono

Satoh

1991

Jpn.J.Pharmacol

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ABSTRACT-The pain response of mice to an injection of 0.5% formalin into the dorsal surface of a hindpaw is biphasic, with a first phase lasting for 5 min and a second phase lasting from 10 to 30 min post-injection. Intrathecal (i.t.) injection of [D-Pro2, D-Trp7'9]-substance P inhibited the first phase, and i.t. cysteamine inhibited the second phase. Lappaconitine (LA) and morphine (MOR) inhibited both phases equally in a dose-dependent manner. Diclofenac inhibited both phases, but the second phase was inhibited by lower doses. An Lt. injection of substance P (SP) or somato statin (SOM) produced a characteristic behavioral response (scratching, biting, and licking). This behavioral response to SP and SOM was inhibited by s.c., intracerebro ventricular (i.c.v.), or Lt. injection of MOR. In contrast, LA inhibited the SP and SOM-induced response when injected s.c. or i.c.v., but had no effect when injected intrathecally. These results indicate that LA may act supraspinally to inhibit the trans mission of nociceptive information by SP and/or SOM.Substance P (SP) and somatostatin (SOM) have been shown to be localized in the dorsal horn of the spinal cord (1, 2) and much evi dence suggests a role for SP and SOM as possible mediators for pain transmission, as reviewed by Sweet (3) and Luttinger et al. (4).The formalin test was originally described in rats and cats by Dubuisson and Dennis (5); the injection of formalin produced a biphasic pain response in rats. Takahashi et al. (6) and Hunskaar et al. (7) reported a slightly modi fied formalin test in mice and examined the effects of many narcotic analgesics, centrally acting non-narcotic analgesics, steroidal antiin flammatory drugs, and non-steroidal antiin flammatory drugs (NSAIDs) (8, 9). Based on these reports, it has been concluded that the biphasic response induced by the injection of formalin reflects the operation of different nociceptive mechanisms. The first phase is due to a direct effect on nociceptors, and the second phase may be due mainly to subse quent inflammation. Takagi and Kuraishi (10), and Kantner et al. (11) showed that SP and SOM were released from the dorsal horn in response to formalin injection, and Ohkubo et al. (12) showed that intrathecal (i.t.) injection of SP antagonist and SP antiserum inhibited only the first phase, while i.t. injection of SOM antagonist and SOM antiserum inhibited only the second phase. These facts indicate that SP is involved in the transmission of the first phase and that SOM is involved in the transmission of the second phase of formalin

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Pharmacological studies of lappaconitine. Analgesia produced by intracerebroventricular, intracisternal and intrathecal injections.

Cited by 20 publications

References 8 publications

Mode of antinociceptive and toxic action of alkaloids of Aconitum spec.

Mode of antinociceptive and toxic action of alkaloids of Aconitum spec.

Pharmacological Studies on Lappaconitine: Possible Interaction with Endogenous Noradrenergic and Serotonergic Pathways to Induce Antinociception.

Pharmacological Studies on Lappaconitine: Antinociception and Inhibition of the Spinal Action of Substance P and Somatostatin.

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