Oral donepezil reduces hypersensitivity after nerve injury by a spinal muscarinic receptor mechanism
ABSTRACT 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.
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ABSTRACT: Although muscarinic acetylcholine (mACh) receptors are expressed in trigeminal ganglia, it is still unknown whether mACh receptors modulate glutamatergic transmission from primary afferents onto medullary dorsal horn neurons. In this study, we have addressed the cholinergic modulation of primary afferent glutamatergic transmission using a conventional whole cell patch clamp technique. Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked from primary afferents by electrical stimulation of trigeminal tract and monosynaptic EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices. Muscarine and ACh reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, muscarine reduced the frequency of miniature EPSCs without affecting the current amplitude, suggesting that muscarine acts presynaptically to decrease the probability of glutamate release onto medullary dorsal horn neurons. The muscarine-induced decrease of glutamatergic EPSCs was significantly occluded by methoctramine or AF-DX116, M2 receptor antagonists, but not pirenzepine, J104129 and MT-3, selective M1, M3 and M4 receptor antagonists. The muscarine-induced decrease of glutamatergic EPSCs was highly dependent on the extracellular Ca(2+) concentration. Physostigmine and clinically available acetylcholinesterase inhibitors, such as rivastigmine and donepezil, significantly shifted the concentration-inhibition relationship of ACh for glutamatergic EPSCs. These results suggest that muscarine acts on presynaptic M2 receptors to inhibit glutamatergic transmission by reducing the Ca(2+) influx into primary afferent terminals, and that M2 receptor agonists and acetylcholinesterase inhibitors could be, at least, potential targets to reduce nociceptive transmission from orofacial tissues.Neuropharmacology 08/2013; DOI:10.1016/j.neuropharm.2013.07.030 · 4.82 Impact Factor
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ABSTRACT: ABSTRACT Alzheimer's disease is an advanced dementia. In this disease, little by little the brain loses most of its functions. Pain is a prevalent complaint. It seems easing the pain had the better recovery to antipsychotic drug in controlling agitation in dementia patients. Donepezil is a drug that is used to treat Alzheimer's disease. This brief report describes an 83-year-old woman with Alzheimer's disease who experienced boredom and changes in attitude for about 1 year and complained about general pain in her extremity. Starting donepezil controlled the patient's symptoms. As soon as the treatment started, all pain was dramatically eliminated and her behavior improved. Donepezil may be effective in controlling the pain and improve the outcome of these patients.Journal of Pain & Palliative Care Pharmacotherapy 01/2014; DOI:10.3109/15360288.2013.876484
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ABSTRACT: Pain is a complex common health problem, with important implications for quality of life and with huge economic consequences. Pain can be elicited due to tissue damage, as well as other multiple factors such as inflammation and oxidative stress. Can there be one therapeutic pathway which may target multiple etiologic factors in pain? In the present article, we review evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and five factors which are etiologic to or protective in pain. Specifically, vagal nerve activity inhibits inflammation, oxidative stress and sympathetic activity, activates brain regions that can oppose the brain "pain matrix", and finally it might influence the analgesic effects of opioids. Together, these can explain the anti-nociceptive effects of vagal nerve activation or of acetylcholine, the principal vagal nerve neurotransmitter. These findings form an evidence-based neurobiological rationale for testing and possibly implementing different vagal nerve activating treatments in pain conditions. Perspective: In this article, we show evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and five factors which are etiologic to pain. Given the evidence and effects of the vagus nerve activation in pain, people involved in pain therapy may need to seriously consider activation of this nerve.The Clinical journal of pain 01/2014; 30(12). DOI:10.1097/AJP.0000000000000071 · 2.70 Impact Factor