The Antiallodynic Effects of Intrathecal Cholinesterase Inhibitors in a Rat Model of Neuropathic Pain

Hwang, Jai‐Hyun; Hwang, Kyu-Sam; Leem, Jeong-Kil; Park, Pyung-Hwan; Han, Sungmin; Lee, Dong-Myung

doi:10.1097/00000542-199902000-00025

Cited by 66 publications

(36 citation statements)

References 39 publications

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“…In the SNL model of neuropathic pain, we demonstrate that WAY-132983 fully reversed the tactile allodynia, a clinical hallmark of neuropathic pain. Although the effects of muscarinic agonists in the SNL model have not been reported previously, our observations are consistent with the reported effects of cholinesterase inhibitors in the SNL model (Lavand'homme et al, 1998;Chiari et al, 1999;Hwang et al, 1999). Furthermore, cholinomimetics reverse the tactile allodynia seen in streptozotocin-induced diabetic rats (Chen et al, 2001), and an increase in mAChR expression levels (Chen and Pan 2003) makes it tempting to speculate that muscarinic agonists may be effective in the treatment of diabetic neuropathy.…”

Section: Discussionsupporting

confidence: 91%

Pharmacological Characterization of the Muscarinic Agonist (3R,4R)-3-(3-Hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983) in in Vitro and in Vivo Models of Chronic Pain

Sullivan¹,

Leventhal²,

Harrison³

et al. 2007

J Pharmacol Exp Ther

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Here, we have investigated the in vitro pharmacology of a muscarinic agonist, (3R,4R)-3-(3-hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983), and we demonstrated its activity in several models of pain. WAY-132983 had a similar affinity for the five muscarinic receptors (9.4 -29.0 nM); however, in calcium mobilization studies it demonstrated moderate selectivity for M 1 (IC 50 ϭ 6.6 nM; E max ϭ 65% of 10 M carbachol-stimulation) over the M 3 (IC 50 ϭ 23 nM; E max ϭ 41%) and M 5 receptors (IC 50 ϭ 300 nM; E max ϭ 18%). WAY-132983 also activated the M 4 receptor, fully inhibiting forskolin-induced increase in cAMP levels (IC 50 ϭ 10.5 nM); at the M 2 receptor its potency was reduced by 5-fold (IC 50 ϭ 49.8 nM). In vivo, WAY-132983 demonstrated good systemic bioavailability and high brain penetration (Ͼ20-fold over plasma levels). In addition, WAY-1329823 produced potent and efficacious antihyperalgesic and antiallodynic effects in rodent models of chemical irritant, chronic inflammatory, neuropathic, and incisional pain. It is noteworthy that efficacy in these models was observed at doses that did not produce analgesia or ataxia. Furthermore, a series of antagonist studies demonstrated that the in vivo activity of WAY-132983 is mediated through activation of muscarinic receptors primarily through the M 4 receptor. The data presented herein suggest that muscarinic agonists, such as WAY-132983, may have a broad therapeutic efficacy for the treatment of pain.Acetylcholine is a major neurotransmitter involved in many physiological processes. Its effects are mediated in part through the five muscarinic acetylcholine receptors (mAChRs; M 1 -M 5 ), which are expressed throughout the CNS and elsewhere (Caulfield and Birdsall, 1998). The M 1 , M 3 , and M 5 receptors are coupled to G q , and they activate phospholipase C, leading to the formation of inositol phosphates, which cause an increase in intracellular calcium. The M 2 and M 4 receptors couple through the inhibitory G proteins, G i/o , and they reduce levels of cAMP through inhibition of adenylate cyclases.The tissue distribution of the mAChRs suggests a potential role for these receptors in pain signaling. For example, mRNA for M 2 , M 3 , and M 4 have been identified in the spinal cord and dorsal root ganglion of rat (Wei et al., 1994;Tata et al., 2000). Furthermore, mAChRs are also expressed in central pain processing areas such as the thalamus, periaqueductal gray, and rostral ventrolateral medulla. A major site of action for cholinomimetics in nociceptive processing is the spinal cord, where they mimic the release of acetylcholine (ACh) from the spinal cholinergic nerves. Noxious pain stimuli are known to increase ACh in the cerebrospinal fluid of Article, publication date, and citation information can be found at

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Section: Discussionsupporting

confidence: 91%

Pharmacological Characterization of the Muscarinic Agonist (3R,4R)-3-(3-Hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983) in in Vitro and in Vivo Models of Chronic Pain

Sullivan¹,

Leventhal²,

Harrison³

et al. 2007

J Pharmacol Exp Ther

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“…In formalin test, choline did have an effect in the second phase. M1 mAChRs in sheep (Bouaziz et al 1995) and rats (Naguib and Yaksh 1997) and M3 mAChRs have been suggested to be involved mainly in spinal antinociception (Hwang et al 1999). nAChRs are extensively distributed in central nervous system (CNS) and peripheral sites.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction

Lima

Costa

Silva

et al. 2016

An. Acad. Bras. Ciênc.

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Geissospermum vellosii (Pao pereira) is a Brazilian tree whose stem barks are rich in indole alkaloids that present intense anticholinesterase activity. The present study evaluated the effects of a stem bark fraction (PPAC fraction) and ethanolic extract (EE) of Pao pereira in classic murine models of infl ammation and pain. The EE and PPAC fraction, both at a dose of 30 mg/kg, signifi cantly reduced mice abdominal constriction induced by acetic acid by 34.8% and 47.5%, respectively. In the formalin test, EE (30 mg/ kg) and PPAC fraction (30 and 60 mg/kg) inhibited only the second phase, by 82.8%, 84.9% and 100%, respectively. Compared with indomethacin, similar doses of EE or PPAC fraction were approximately twice as effective in causing antinociception. PPAC fraction was not effective in the hot plate test but reduced the infl ammatory response at the second (50.6%) and third (57.8%) hours of rat paw edema induced by carrageenan. Antihyperalgesic activity was observed within 30 min with a peak at 2 h (60.1%). These results demonstrate that compounds in PPAC fraction have anti-infl ammatory and antinociceptive activity by a mechanism apparently unrelated to the opioid system. Regardless of similar responses to indomethacin, the effects of PPAC fraction are mainly attributed to acetylcholine actions.

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“…1 7 A previous study suggested that muscarinic stimulation of critical spinal sites resulted in the activation of local lumbar cholinergic circuits that might modulate the local transmission of the afferent allodynic information. 8 Considerable evidence exists that the muscarinic cholinergic system of the lumbar spinal cord is intrinsic 18,19 and that the cholinergic innervation of the intermediolateral cell column (IML) is from a source intrinsic to the spinal cord. 19,20 A recent study by Pan et al, 7 found that spinally released acetylcholine plays a role in the antiallodynic effect of IT clonidine in neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 IT administration of cholinesterase inhibitors displays a dose-dependent antiallodynic effect, which is mediated by the spinal muscarinic receptor system. 8 Carbachol is a nonspecific cholinergic agonist with a prominent muscarinic effect. 9 Owing to the hydrophilic properties of carbachol it may have a long duration of action after IT administration.…”

mentioning

confidence: 99%

Intrathecal carbachol and clonidine produce a synergistic antiallodynic effect in rats with a nerve ligation injury

Lee

Sim

Park

et al. 2002

Can J Anesth/J Can Anesth

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Purpose: Antiallodynic effects have been demonstrated after intrathecal administration of a-2 adrenoceptor agonists and cholinesterase inhibitors in rats. Intrathecal carbachol also increases the activity of cholinergic receptor system at the spinal level. However, there is no study regarding the antagonism of carbachol on touch-evoked allodynia and the interaction with clonidine. This study examines the intrathecal interaction between two drugs in a rat model of nerve ligation injury.Methods: Rats were prepared with tight ligation of the left L5-6 spinal nerves and chronic intrathecal catheter implantation. Tactile allodynia was measured by using application of von Frey filaments to the lesioned hindpaw. Carbachol (0.3-10 µg) and clonidine (1-30 µg) were administered to obtain the dose-response curves and the 50% effective dose (ED 50 ) for each drug. Fractions of ED 50 values (½, 1/4, 1/8, and 1/16) were administered intrathecally to establish the ED 50 of the carbachol-clonidine combination. Isobolographic and fractional analyses of drug interaction were performed.Results: Intrathecal carbachol and clonidine alone produced a dose-dependent reduction of tactile allodynia without severe motor weakness or sedation. A carbachol-clonidine combination produced a dose-dependent increase in withdrawal threshold of the lesioned hindpaw with a reduced incidence and magnitude of side effects. Both analyses revealed a synergistic interaction after the coadministration of carbachol and clonidine.Conclusions: This study indicates that carbachol, like clonidine, provides a moderate antagonism on touch-evoked allodynia at the spinal level. The results suggest that intrathecally administered carbachol is synergistic when combined with clonidine.

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The Antiallodynic Effects of Intrathecal Cholinesterase Inhibitors in a Rat Model of Neuropathic Pain

Cited by 66 publications

References 39 publications

Pharmacological Characterization of the Muscarinic Agonist (3R,4R)-3-(3-Hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983) in in Vitro and in Vivo Models of Chronic Pain

Pharmacological Characterization of the Muscarinic Agonist (3R,4R)-3-(3-Hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983) in in Vitro and in Vivo Models of Chronic Pain

Antinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction

Intrathecal carbachol and clonidine produce a synergistic antiallodynic effect in rats with a nerve ligation injury

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