Central and Peripheral Analgesia Mediated by the Acetylcholinesterase-Inhibitor Neostigmine in the Rat Inflamed Knee Joint Model

Buerkle, Hartmut; Boschin, Matthias; Marcus, Marianne T.; Brodner, G.; Wüsten, R.; Aken, Hugo Van

doi:10.1213/00000539-199805000-00023

“…It has been reported that intra-articular administration of neostigmine in inflamed rat knees promoted dose-dependent antinociception that was antagonized by atropine injected at the same site, but not when administered intrathecally [37] .…”

Section: Discussionmentioning

confidence: 99%

Peripheral Control of Inflammatory but Not Neuropathic Pain by Endogenous Cholinergic System

Motta¹,

Perez²,

Alves³

et al. 2011

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This study investigated the role of the cholinergic system in the modulation of inflammatory and neuropathic pain. The paw pressure test was used with inflammatory pain induced by intraplantar injection of carrageenan and neuropathic pain induced by sciatic nerve constriction. All drugs were locally administered into the right hindpaw of rats. Neostigmine, an acetylcholinesterase inhibitor (2, 4, 8 or 16 µg), inhibited the inflammatory pain induced by carrageenan (250 µg/paw), but not the hyperalgesia induced by prostaglandin E₂ (2 µg/paw). Neostigmine (8 µg) increased the nociceptive threshold only in the treated paw, suggesting only a local effect. The muscarinic antagonist atropine (150, 300 and 600 µg) caused a reduction in the nociceptive threshold induced by carrageenan (125 µg/paw), but not by prostaglandin E₂ (1 µg/paw). Atropine significantly decreased the nociceptive threshold only in the treated paw. On the other hand, in the presence of neuropathic pain, atropine (300 µg) did not alter the nociceptive threshold induced by constriction of the sciatic nerve. This study suggests that a peripheral endogenous cholinergic system involving muscarinic receptors may be activated during inflammation as a modulatory negative feedback control of inflammatory pain.

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“…While some work has suggested that analgesia and sedation may be separable if different sub-classes of α 2 receptors can be targeted [98, 105, 106], such differentiation is not supported by studies in gene-altered mice [107], and the work has not led to definitively distinguishable agents. The cLogP of clonidine (2.6) and dexmedetomidine (3.0) reflect upon the short duration of action and rapid systemic exposure that occurs with these spinal agents suggesting that a more polar α 2 agonist might have virtue.…”

Section: Current Spinal Agentsmentioning

confidence: 99%

“…Neostigmine is a cholinesterase inhibitor that yields antinociceptive effects in a variety of preclinical models [106, 271-275] in several species such as rodents and sheep [276]. Bolus intrathecal delivery of neostigmine has been reported in humans to have significant effects upon postoperative pain [277-279].…”

Section: Current Spinal Agentsmentioning

confidence: 99%

Current and Future Issues in the Development of Spinal Agents for the Management of Pain

Yaksh

¹

,

Fisher²,

Hockman³

et al. 2017

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.

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“…Neostigmine is a cholinesterase inhibitor that yields antinociceptive effects in a variety of preclinical models [106,[271][272][273][274][275] in several species such as rodents and sheep [276]. Bolus intrathecal delivery of neostigmine has been reported in humans to have significant effects upon postoperative pain [277][278][279].…”

Section: Spinal Cholinesterase Inhibitorsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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Central and Peripheral Analgesia Mediated by the Acetylcholinesterase-Inhibitor Neostigmine in the Rat Inflamed Knee Joint Model

Cited by 46 publications

References 21 publications

Peripheral Control of Inflammatory but Not Neuropathic Pain by Endogenous Cholinergic System

Peripheral Control of Inflammatory but Not Neuropathic Pain by Endogenous Cholinergic System

Current and Future Issues in the Development of Spinal Agents for the Management of Pain

Current and Future Issues in the development of spinal agents for the management of pain

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