Behavioral and Molecular Basis of Cholinergic Modulation of Pain: Focus on Nicotinic Acetylcholine Receptors

Toma, Wisam; Ulker, Esad; Alqasem, Mashael; AlSharari, Shakir D.; McIntosh, J. Michael; Damaj, M. Imad

doi:10.1007/7854_2020_135

Cited by 14 publications

(14 citation statements)

References 98 publications

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“…The other important area for potential therapeutic development is the management of neuropathic and inflammatory pain, , a direction supported by numerous studies with the α9α10-selective conotoxins. ,,− While these conotoxin studies point to the inhibition of α9α10 receptors as the therapeutic modality, an alternative perspective from work with phosphocholine , suggests that atypical agonism of α9 receptors may be the basis for the anti-inflammatory effects of α9 drugs. It has been previously demonstrated that p -CF 3 , a compound we have identified as a partial agonist for both α7 and α9, was effective at reducing inflammatory and neuropathic pain in an animal model …”

Section: Results and Discussionmentioning

confidence: 99%

“…41 It has been proposed that an α9α10 antagonist, probably in conjunction with a central nervous system agent, could be used to treat this condition. 37 The other important area for potential therapeutic development is the management of neuropathic and inflammatory pain, 42,43 a direction supported by numerous studies with the α9α10-selective conotoxins. 28,29,44−47 While these conotoxin studies point to the inhibition of α9α10 receptors as the The values "n" are the Hill coefficients of the fits.…”

Section: ■ Introductionmentioning

confidence: 99%

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Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Papke

Andleeb

Stokes

et al. 2022

ACS Chem. Neurosci.

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Nicotinic acetylcholine receptors containing α9 subunits are essential for the auditory function and have been implicated, along with α7containing nicotinic receptors, as potential targets for the treatment of inflammatory and neuropathic pain. The study of α9-containing receptors has been hampered by the lack of selective agonists. The only α9-selective antagonists previously identified are peptide conotoxins. Curiously, the activity of α7 and α9 receptors as modulators of inflammatory pain appears to not rely strictly on ion channel activation, which led to the identification of α7 "silent agonists" and phosphocholine as an "unconventional agonist" for α9 containing receptors. The parallel testing of the α7 silent agonist p-CF 3 −diEPP and phosphocholine led to the discovery that p-CF 3 −diEPP was an α9 agonist. In this report, we compared the activity of α7 and α9 with a family of structurally related compounds, most of which were previously shown to be α7 partial or silent agonists. We identify several potent α9-selective agonists as well as numerous potent and selective α9 antagonists and describe the structural basis for these activities. Several of these compounds have previously been shown to be effective in animal models of inflammatory pain, an activity that was assumed to be due to α7 silent agonism but may, in fact, be due to α9 activity. The α9-selective conotoxin antagonists have also been shown to reduce pain in similar models. Our identification of these new α9 agonists and antagonists may prove to be invaluable for defining an optimal approach for treating pain, allowing for reduced use of opioid drugs.

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Section: Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Papke

Andleeb

Stokes

et al. 2022

ACS Chem. Neurosci.

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“…In addition, acetylcholine receptors have emerged as a novel therapeutic target for pain in recent years. Allosteric modulators and silent agonists for acetylcholine receptors have shown to have potential for reducing chronic pain ( Toma et al, 2020 ).…”

Section: Dcloud Theorymentioning

confidence: 99%

Analgesic Alkaloids Derived From Traditional Chinese Medicine in Pain Management

et al. 2022

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Chronic pain is one of the most prevalent health problems. The establishment of chronic pain is complex. Current medication for chronic pain mainly dependent on anticonvulsants, tricyclic antidepressants and opioidergic drugs. However, they have limited therapeutic efficacy, and some even with severe side effects. We turned our interest into alkaloids separated from traditional Chinese medicine (TCM), that usually act on multiple drug targets. In this article, we introduced the best-studied analgesic alkaloids derived from TCM, including tetrahydropalmatine, aloperine, oxysophocarpine, matrine, sinomenine, ligustrazine, evodiamine, brucine, tetrandrine, Stopholidine, and lappaconitine, focusing on their mechanisms and potential clinical applications. To better describe the mechanism of these alkaloids, we adopted the concept of drug-cloud (dCloud) theory. dCloud illustrated the full therapeutic spectrum of multitarget analgesics with two dimensions, which are “direct efficacy”, including inhibition of ion channels, activating γ-Aminobutyric Acid/opioid receptors, to suppress pain signal directly; and “background efficacy”, including reducing neuronal inflammation/oxidative stress, inhibition of glial cell activation, restoring the balance between excitatory and inhibitory neurotransmission, to cure the root causes of chronic pain. Empirical evidence showed drug combination is beneficial to 30–50% chronic pain patients. To promote the discovery of effective analgesic combinations, we introduced an ancient Chinese therapeutic regimen that combines herbal drugs with “Jun”, “Chen”, “Zuo”, and “Shi” properties. In dCloud, “Jun” drug acts directly on the major symptom of the disease; “Chen” drug generates major background effects; “Zuo” drug has salutary and supportive functions; and “Shi” drug facilitates drug delivery to the targeted tissue. Subsequently, using this concept, we interpreted the therapeutic effect of established analgesic compositions containing TCM derived analgesic alkaloids, which may contribute to the establishment of an alternative drug discovery model.

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“…Despite the encouraging therapeutic efficacy of α7 nAChR agonists in chronic pain, concerns have been raised regarding the long-term administration of α7 nAChR agonists due to rapid desensitization of α7 nAChR, receptor selectivity issues, and the narrow window of antinociceptive effect in vivo (Freitas et al, 2013a;Toma et al, 2020). These limitations hinder the application of α7 nAChR as analgesics in the clinic.…”

Section: α Nachr Positive Allosteric Modulatorsmentioning

confidence: 99%

“…However, they led to the development of α7 nAChR positive allosteric modulators (PAMs), which potentiate α7 currents in the presence of an endogenous agonist such as acetylcholine and choline. Type I PAMs facilitate agonist response with little effect on desensitization of α7 nAChRs, while type II PAMs facilitate agonist response and retard the obvious desensitization profile of the agonist response (Toma et al, 2020). Freitas et al (2013b) investigated two types of PAMs in chronic pain models.…”

Section: α Nachr Positive Allosteric Modulatorsmentioning

confidence: 99%

Targeting α7 nicotinic acetylcholine receptors for chronic pain

Zhou

Liu²,

Liu³

et al. 2022

Front. Mol. Neurosci.

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Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

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Behavioral and Molecular Basis of Cholinergic Modulation of Pain: Focus on Nicotinic Acetylcholine Receptors

Cited by 14 publications

References 98 publications

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors

Analgesic Alkaloids Derived From Traditional Chinese Medicine in Pain Management

Targeting α7 nicotinic acetylcholine receptors for chronic pain

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