Cholinesterase inhibitors which reach the central nervous system produce pain relief but are poorly tolerated because of gastrointestinal side effects. Here, the authors tested whether donepezil, a central nervous system penetrant cholinesterase inhibitor with a low incidence of gastrointestinal side effects, would relieve hypersensitivity in an animal model of neuropathic pain.
Male rats were anesthetized, and the L5 and L6 spinal nerves were ligated unilaterally. Hypersensitivity was measured by withdrawal threshold to von Frey filament application to the hind paw after oral donepezil, and antagonists administered centrally and peripherally. Efficacy of chronic oral donepezil to relieve hypersensitivity was tested, and activation of G proteins by M(2) muscarinic receptors was determined by carbachol-stimulated [(35)S]guanosine triphosphate (gamma)S autoradiography in brain and spinal cord.
Spinal nerve ligation resulted in hypersensitivity that was more severe ipsilateral than contralateral to surgery. Oral donepezil reduced hypersensitivity bilaterally in a dose-dependent manner for 2 h, and this effect was blocked by spinal but not supraspinal or peripheral muscarinic receptor antagonism. Oral donepezil maintained efficacy over 2 weeks of twice daily administration, and this treatment did not lead to desensitization of muscarinic receptor-coupled G proteins in brain or spinal cord.
Donepezil, a well-tolerated cholinesterase inhibitor used in the treatment of Alzheimer dementia, reduces hypersensitivity in this rat model of neuropathic pain by actions on muscarinic receptors in the spinal cord. Lack of tolerance to this effect, in contrast to rapid tolerance to direct receptor agonists, suggests that cholinesterase inhibition may be useful in the treatment of neuropathic pain.
"Chronically administered AChE inhibitors did not desensitize muscarinic receptor function in a number of studies. Fourteen days of Donepezil (10 mg/kg twice daily) did not desensitize muscarinic receptor-coupled G proteins in rat brain or spinal cord  "
[Show abstract][Hide abstract] ABSTRACT: Donepezil, an acetylcholinesterase (AChE) inhibitor used for treating Alzheimer's disease patients, is thought to act by increasing brain extracellular acetylcholine (ACh), and ACh binding to cholinergic receptors. Muscarinic receptors are coupled to cytosolic phospholipase A2 (cPLA2) activation and arachidonic acid (AA) release from synaptic membrane phospholipid. This activation can be imaged in rodents as an AA incorporation coefficient k*, using quantitative autoradiography. Acute and chronic effects of donepezil on the AA signal, k* for AA, were measured in 81 brain regions of unanesthetized rats. Twenty min after a single oral dose (3.0 mg/kg) of donepezil, k* was increased significantly in 37 brain regions, whereas k* did not differ from control 7 h afterwards or following chronic (21 days) of donepezil. Pretreatment with atropine prevented the 20-min increments in k* following donepezil. Donepezil also increased the brain ACh concentration and reduced brain AChE activity, but did not change cPLA2 activity, regardless of administration regimen. These results show that donepezil acutely increases the brain AA signal that is mediated by ACh acting at muscarinic receptors, but that this signal is rapidly desensitized despite continued elevated brain ACh concentration. In contrast, the AA signal in response to arecoline was not altered following donepezil.
"If gabapentin analgesia depends on the activation of a spinal noradrenergic-cholinergic circuit, its potency should be enhanced by amplifying the effects of these neurotransmitters. We recently reported that oral administration of the cholinesterase inhibitor donepezil reduces hypersensitivity by spinal muscarinic receptor activation (Clayton et al., 2007), and that oral gabapentin and donepezil interact in a strongly synergistic manner after peripheral nerve injury in rats (Hayashida et al., 2007b). Duloxetine, an approved serotonin / noradrenaline re-uptake inhibitor for the treatment of diabetic peripheral neuropathic pain (Goldstein et al., 2005), should also enhance the noradrenergic-cholinergic circuit activated by gabapentin. "
[Show abstract][Hide abstract] ABSTRACT: We previously reported that gabapentin activates the bulbospinal-spinal noradrenergic-cholinergic pathway to produce analgesia in rats after nerve injury. Also, gabapentin interacts synergistically with a cholinesterase inhibitor donepezil to produce analgesia. Duloxetine, a serotonin/noradrenaline re-uptake inhibitor, has been used for the treatment of neuropathic pain and should amplify the noradrenergic mechanisms recruited by gabapentin. In the present study, we determined the interaction between duloxetine and gabapentin with and without donepezil when administered by the clinically preferred oral route in rats after spinal nerve ligation. The ED(50) value of gabapentin, donepezil, and duloxetine to reduce mechanical hypersensitivity after nerve injury was 45, 3.7, and 32 mg/kg, respectively. In the examination of two drug combinations, oral duloxetine with either gabapentin or donepezil were additive to reduce hypersensitivity. The combination of all three drugs yielded a synergistic interaction with an observed ED(50) at 1/4th the predicted dose of additivity, likely due to the gabapentin-donepezil interaction. This three drug combination did not affect motor coordination or show signs of sedation in the rotarod test. Analgesia by the combination of these three drugs was reversed by intrathecal injection either of the alpha(2)-adrenoceptor antagonist idazoxan or by the muscarinic receptor antagonist atropine. These results suggest that the combination of these drugs, which stimulate and augment the bulbospinal-spinal noradrenergic-cholinergic pathway, lowers the dose requirement for each drug to reduce hypersensitivity after nerve injury without sedative effects. The current study provides the rationale for clinical study of the combination of gabapentin, donepezil and duloxetine to treat neuropathic pain.
European Journal of Pharmacology 10/2008; 598(1-3):21-6. DOI:10.1016/j.ejphar.2008.09.004 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Agent-based systems add unique aspects to assessment activity and require the use of traditional tools and techniques in new or unconventional ways and the development of new, domain-customized tools. Agent-based system assessments must address the same issues as those of traditional systems: unsafe programming practices, such as failure to validate inputs or use of insecure libraries. Assessments of agent-based systems should also include "system-of-systems" concepts. Complex systems interact with and rely on other systems that may exist independently. A system-of-systems assessment identifies systems and their behaviors and considers ways that those behaviors can interact to harm the complex system. Attacks are then developed to cause the desired behavior. Agent-based systems are aware of and respond to their environment through adaptation and evolution. They require assessment through concepts normally reserved for humans. Just as adversaries cause humans to react in ways advantageous to the attacker, agent-based system assessors must cause agents to react. These assessments require "social engineering" of the agents just as simpler systems may require "social engineering" of users and administrators. This paper discusses the application of existing and new tools and techniques to agent system assessments including descriptions of actual and theoretical attacks.
Multi-Agent Security and Survivability, 2004 IEEE First Symposium on; 09/2004
Yu-Ting L Dingle, Molly Elizabeth Boutin, Anda M Chirila, Liane L Livi, Nicholas R Labriola, Lorin M Jakubek, Jeffrey R Morgan, Eric M Darling, Julie A Kauer, Diane Hoffman-Kim
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