Relief of Hypersensitivity after Nerve Injury from Systemic Donepezil Involves Spinal Cholinergic and γ-Aminobutyric Acid Mechanisms

Abstract

Background: Evoking spinal release of acetylcholine (ACh) produces antinociception in normal animals and reduces hypersensitivity after nerve injury, and some studies suggest that ACh-mediated analgesia relies on γ-aminobutyric acid (GABA)-ergic signaling in the spinal cord. In this study, the authors tested the spinal mechanisms underlying the antihypersensitivity effects of donepezil, a central nervous system-penetrating cholinesterase inhibitor, in a rat model of neuropathic pain. Methods: Male Sprague-Dawley rats were anesthetized, and L5 spinal nerve ligation was performed unilaterally. Withdrawal threshold to a paw pressure test was measured before and after intraperitoneal administration of donepezil, with or without intrathecal antagonists for cholinergic and GABAergic receptors. Microdialysis studies in the ipsilateral dorsal horn of the lumbar spinal cord were also performed to measure extracellular ACh and GABA. Results: Donepezil increased the withdrawal threshold in spinal nerve ligation rats but not in normal rats. The antihypersensitivity effect of donepezil (1 mg/kg) in spinal nerve ligation rats was reduced by intrathecal pretreatment with atropine (30 μg), a muscarinic receptor antagonist; mecamylamine (100 μg), a nicotinic receptor antagonist; bicuculline (0.03 μg), a γ-aminobutyric acid receptor type

Donepezil Reverses Intermittent Stress-Induced Generalized Chronic Pain Syndrome in Mice

“…This study showed that donepezil inhibits ICS-induced fibromyalgia-like pain via supraspinal mechanisms, whereas it blocks neuropathic pain via spinal mechanisms (Kimura et al, 2013). Such different pharmacotherapeutical actions against neuropathic pain and ICS-induced fibromyalgia-like pain can be observed in gabapentinoid actions, as described above.…”

Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception

“…In a rat model of spinal nerve ligation (SNL), donepezil administration results in an attenuation of mechanical hyperalgesia through a spinal muscarinic mechanism (Clayton et al, 2007). This analgesic effect could also involve spinal nicotinic and GABAergic receptors, but it is still unclear whether this effect of donepezil is directly due to an increase of spinal Ach release (Kimura et al, 2013). Indeed, cholinergic analgesia is only observed in neuropathic pain conditions, but the peak level and the time course of the Ach increase after donepezil treatment using spinal microdialysis were similar between normal and SNL rats (Kimura et al, 2013).…”

“…This analgesic effect could also involve spinal nicotinic and GABAergic receptors, but it is still unclear whether this effect of donepezil is directly due to an increase of spinal Ach release (Kimura et al, 2013). Indeed, cholinergic analgesia is only observed in neuropathic pain conditions, but the peak level and the time course of the Ach increase after donepezil treatment using spinal microdialysis were similar between normal and SNL rats (Kimura et al, 2013). Furthermore, the spinal basal levels of ACh were not significantly different between normal and SNL rats.…”

“…Therefore, in a neuropathic pain context, antinociception could be achieved by using centrally active cholinesterase inhibitors, which would result in an increased brain Ach concentration, ultimately leading to the activation of upregulated cortical pIC M2 receptors. The change of M2 expression could be a key point in the analgesic effect of donepezil rather than Ach availability (Hayashida et al, 2006;Kimura et al, 2013).…”

“…Moreover, acute donepezil administration 1 month after nerve injury largely reduced mechanical allodynia in SNI rats. Several preclinical studies have already established the interest of donepezil and other cholinesterase inhibitors for the treatment of neuropathic pain (Clayton et al, 2007;Kimura et al, 2013). In a rat model of spinal nerve ligation (SNL), donepezil administration results in an attenuation of mechanical hyperalgesia through a spinal muscarinic mechanism (Clayton et al, 2007).…”