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

Ono, Mamoru; Satoh, Tetsuo

doi:10.1254/jjp.55.523

Cited by 19 publications

(10 citation statements)

References 32 publications

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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%

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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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Section: Discussionsupporting

confidence: 47%

“…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).…”

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confidence: 99%

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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“…Despite the mode of action, we proved lappaconitine to be antinociceptive with an ED 50 of 2.7 mg/kg (i.v. ), a value close to that (2.5 mg/kg, s.c., mice) of Ono and Satoh (1991). Although the ED 50 and LD 50 values calculated for the antinociceptive properties and acute toxicity of lappaconitine were about 100-fold higher than those of aconitine, the affinity of lappaconitine (K i 11.5 µM) for site II was only 10 times lower than that of aconitine (K i 1.4 µM).…”

Section: Discussionmentioning

confidence: 89%

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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“…Formalininduced release of substance P into the dorsal horn parallels behavioral nociceptive responses and electrical activity of dorsal horn neurons (38)(39)(40)(41), suggesting that substance P may be important in the transmission of the nociceptive signal. On the other hand, tachykinin receptor antagonists have not consistently shown a clear involvement of substance P in formalin-induced pain; some investigators found antagonisteffects primarily during the early phase (42,43), while others found effects during the late phase (44-47), or both phases (48,49). The interpretation of the pharmacological data is further complicated by the fact that some antagonists exhibit NK1 receptor independent effects (50) and may also affect motor behaviors that can interfere with the behavioral test (51).…”

Section: Discussionmentioning

confidence: 99%

Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene

Zimmer

Baffi

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

198

103

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The tachykinin neuropeptides, substance P and substance K, are produced in nociceptive primary sensory neurons and in many brain regions involved in pain signaling. However, the precise role and importance of these neuropeptides in pain responses has been debated. We now show that mice that cannot produce these peptides display no significant pain responses following formalin injection and have an increased pain threshold in the hotplate test. On the other hand, the mutant mice react normally in the tail f lick assay and acetic acid-induced writhing tests. These results demonstrate that substance P and͞or substance K have essential functions in specific responses to pain.The tachykinins are a family of structurally related neuropeptides. In the mouse, they are encoded by the genes Tac1 and Tac2. Tac1 produces substance P, substance P (neurokinin A), neurokinin A (3-10), neuropeptide K, and neuropeptide ␥ as a result of differential splicing and posttranslational processing (1-4). Tac2 produces the peptide neurokinin B.The undecapeptide substance P was first detected by von Euler and Gaddum (5) in 1931. Its structure was revealed by Leeman and her coworkers (6, 7) in 1971. The Tac1 cDNA was cloned in 1983 by Nakanishi and his coworkers (2,8). The Tac1 gene is expressed in many regions in the central and peripheral nervous system, as well as in nonneuronal tissues. Substance P has been implicated in a variety of physiological processes including cardiovascular, respiratory, and gastrointestinal functions; inflammatory responses; and nociception. In addition, Hunt and coworkers have suggested that substance P may be involved in axon guidance during embryonic development (9).The precise role of substance P in these processes is unclear. For example, substance P is synthesized in nociceptive primary sensory neurons, which send C-and A␦ fibers to dorsal horn projection neurons in lamina I and IV-V, and to nociceptionspecific interneurons in lamina II-III of the spinal cord. Axons of projection neurons terminate in many supraspinal nuclei that are involved in pain transmission (10, 11). Nociceptive stimulation triggers the release of substance P from C-afferent terminals in the marginal layers of the spinal cord (12), evokes slow excitatory postsynaptic potentials in second-order sensory neurons in the dorsal horn, and facilitates their activation (13). These data, together with other functional evidence (11,14), indicated an important role for substance P in the processing of nociceptive signals.We have begun to use a genetic approach to study the functions of tachykinin peptides. As a first step, we have generated mice with a targeted mutation in the Tac1 gene. These mice are viable and fertile, but exhibit striking defects in nociceptive behaviors. MATERIALS AND METHODS Generation and Breeding of Tac1؊͞؊ Mice. Tac1 mutations were established by homologous recombination in MPI2 embryonic stem (ES) cells according to standard protocols (15). One mutant ES cell line was used to derive chimeras by morula aggrega...

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

Cited by 19 publications

References 32 publications

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

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

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

Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene

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