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Treatment of Chronic Neuropathic Pain

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Treatment of Chronic Neuropathic Pain Narrative Review Treatment of chronic neuropathic pain: purine receptor modulation Kenneth A. Jacobsona, Luigino Antonio Giancottib, Filomena Laurob, Fatma Muftib, Daniela Salveminib,* 06/11/2020 on 3U6Qur4PG8Cp3fhvloi8qBpY7fujG3dPKasYMD+lWJpib/J9/jG1M3P5/SdPwJzQZopI9kkCkONW3pMktyxp4tovfFowndLubZk7zJkoatOlb7XXAf6/mu3JhfuJ6/VZKl/sopHhTqbQ4RCp2fMF2A== by https://journals.lww.com/pain from Downloaded Downloaded Abstract from https://journals.lww.com/pain Extracellular nucleosides and nucleotides have widespread functions in responding to physiological stress. The “purinome” encompasses 4 G-protein-coupled receptors (GPCRs) for adenosine, 8 GPCRs activated by nucleotides, 7 adenosine 59-triphosphate-gated P2X ion channels, as well as the associated enzymes and transporters that regulate native agonist levels. Purinergic signaling modulators, such as receptor agonists and antagonists, have potential for treating chronic pain. Adenosine and its analogues potently suppress nociception in preclinical models by activating A1 and/or A3 adenosine receptors (ARs), but safely harnessing this pathway to clinically treat pain has not by 3U6Qur4PG8Cp3fhvloi8qBpY7fujG3dPKasYMD+lWJpib/J9/jG1M3P5/SdPwJzQZopI9kkCkONW3pMktyxp4tovfFowndLubZk7zJkoatOlb7XXAf6/mu3JhfuJ6/VZKl/sopHhTqbQ4RCp2fMF2A== been achieved. Both A2AAR agonists and antagonists are efficacious in pain models. Highly selective A3AR agonists offer a novel approach to treat chronic pain. We have explored the structure activity relationship of nucleoside derivatives at this subtype using a computational structure-based approach. Novel A3AR agonists for pain control containing a bicyclic ring system (bicyclo [3.1.0] hexane) in place of ribose were designed and screened using an in vivo phenotypic model, which reflected both pharmacokinetic and pharmacodynamic parameters. High specificity (.10,000-fold selective for A3AR) was achieved with the aid of receptor homology models based on related GPCR structures. These A3AR agonists are well tolerated in vivo and highly efficacious in models of chronic neuropathic pain. Furthermore, signaling molecules acting at P2X3, P2X4, P2X7, and P2Y12Rs play critical roles in maladaptive pain neuroplasticity, and their antagonists reduce chronic or inflammatory pain, and, therefore, purine receptor modulation is a promising approach for future pain therapeutics. Structurally novel antagonists for these nucleotide receptors were discovered recently. Keywords: Adenosine receptor, P2Y receptor, P2X receptor, Pain, Agonist, Antagonist 1. Introduction Purine receptors belong to a ubiquitous signaling system in the Fig. 1 78,185 Chronic pain treatment remains one of the major unsolved medical body that has been termed the “purinome” ( ). Adenosine needs and also accompanies many diseases and pharmacological 59-triphosphate and other adenine nucleotides are released during interventions. Ion channels, G-protein-coupled receptors (GPCRs), physiological stress, stemming from oxygen and nutrient depriva- and kinases are common targets for analgesic drug discovery. tion, inflammation, cancer, tissue injury, etc., which are ultimately However, modulators of purine receptors (either GPCRs or catabolized to adenosine. The immediate response to the stress is 26,151 activation by ATP of P2X receptors to open ligand-gated cation adenosine 59-triphosphate [ATP]-gated channels) are less often considered in pain research, compared to widely used channels. Each functional P2X ion channel consists of a homomer treatments: sodium and calcium channel blockers, g-aminobutyric or heterotrimer of P2X subunits. A more diverse set of adenine and acid (GABA) modulators, ligands of opioid and cannabinoid uracil nucleotides activate the 8 G-protein-coupled P2Y receptors receptors, and kinase inhibitors.31 Nevertheless, the existing treat- (P2YRs), including nucleoside 59-diphosphates, 59-triphosphates, ments are not generally effective in most patients, and the current and uridine diphosphate (UDP)-sugars. There are 8 P2Y receptor treatments develop tolerance or have other serious side-effect subtypes (P2Y1,P2Y2,P2Y4,P2Y6,P2Y11,P2Y12,P2Y13,and liabilities upon prolonged use. For example, opiates are more P2Y14) and 7 P2X receptor subunits (P2X1-7) that comprise an effective in acute pain than in chronic pain and can lead to addiction, active trimeric channel. The P2X and P2Y receptors tend to boost the immune response in response to nucleotides, with their ligands desensitization, and even hyperalgesia. Thus, novel treatment 32 approaches for chronic neuropathic pain are needed. acting as immediate danger signals. Nucleotide-induced pain is included in this scheme as a beneficial function because pain is on 06/11/2020 a critical survival mechanism. Subsequent activation of adenosine Sponsorships or competing interests that may be relevant to content are disclosed receptors (ARs), also known as P1 receptors, of which there are 4 at the end of this article. subtypes (A1,A2A,A2B,andA3), in general tends to put the brakes a Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of on the immune response, and their activation functions endoge- Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, United States, nously to suppress pain. This signaling system represents b Department of Pharmacology and Physiology, Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, MO, United States a temporal sequence of first activation of proinflammatory P2Rs *Corresponding author. Address: Department of Pharmacology and Physiology, by nucleotides, followed by the prolonged anti-inflammatory effect Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO of adenosine, mainly formed gradually by enzymatic hydrolysis of 63104, United States. Tel.: 314-977-6430; fax: 314-977-6411. E-mail address: released ATP, at the ARs.32 Thus,inmanycases,actionofP2Rs [email protected] (D. Salvemini). increase, and ARs decrease, pain signaling.26,124 Therefore, often, PAIN 00 (2020) 1–17 but not always, P2R antagonists and AR agonists are sought for © 2020 International Association for the Study of Pain controlling pain. RNA-seq (RNA-sequencing) analysis has shown http://dx.doi.org/10.1097/j.pain.0000000000001857 that the expression of many of these genes in the purinome is Month 2020· Volume 00· Number 00 www.painjournalonline.com 1 Copyright © 2020 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. 2 K.A. Jacobson et al.·00 (2020) 1–17 PAIN® Figure 1. Purinergic signaling pathways for purine nucleosides and nucleotides, and pyrimidine nucleotides. Extracellular ATP and other nucleotides originate from intracellular sources through cell damage, cotransmission, pannexin hemichannels, and other mechanisms. These nucleotides act on P2Y (GPCRs, activated by triphosphates, diphosphates, and UDP-sugars) and P2X (ion channels, mainly by ATP) receptors. Ectonucleotidases (CD39 and CD73) are largely responsible for the formation, from ATP, of adenosine that activates its 4 receptors. In general, adenosine receptor agonists and P2X/P2Y receptor antagonists induce pain relief in various models. enhanced in the dorsal root ganglia (DRG) and the spinal cord (SC) microenvironment can promote activation of the P2XRs by known (Table 1).146 phenomenon of pH modulation of the receptor protein.39 Many compounds are now available as selective modulators of the purinergic system, either as directly acting agonists and 2.1. P2X3R antagonist antinociceptive effects antagonists of P2Rs (Fig. 2)orARs(Figs. 3 and 4),78 or as inhibitors Both pharma and academic laboratories have maintained a long-term of associated enzymes and transporters that regulate native levels of effort to produce a P2X3R antagonist that might be effective in adenosine (Fig. 4) or nucleotides. Inhibitors of enzymes involved in controlling pain.23,75,165,172 However, there are currently no P2X3 processing of adenosine include the widely used adenosine kinase antagonists in clinical trials for pain, but one is in trials for chronic inhibitors ABT-702 38, a pyridopyrimidine, and the nucleoside A- cough.133 Various P2X3 antagonists have been reported,64 including 134974 39 (Fig. 3).87 Inhibitors of these enzymes and transporters, A-317491 9, which is potent and selective but not orally bioavailable. in some cases, are approved drugs. For example, adenosine This first-reported selective P2X3R antagonist reduces neuropathic, deaminase (ADA) inhibitor, pentostatin (deoxycoformycin) 44,isan inflammatory, and chemogenic pain after intrathecal or intraplantar anticancer drug. Dipyridamole 43, a clinical vasodilator, inhibits administration.128 P2X3R antagonists have been shown to be equilibrative nucleoside transporters 1 and 2 (ENT1/2) and also acts efficacious in reducing chronic pain in animal models of cancer54,93 as a phosphodiesterase (PDE) inhibitor. and in several animal models of neuropathic pain such as chronic constriction injury (CCI) of sciatic nerve,152 spinal nerve injury,66 partial ligation of the unilateral infraorbital nerve,154 chronic pancreatitis,188 2. P2XR ligands and their use in relieving chronic pain maternal separation,198 and inflammatory pain.86,90 Recently, nucle- 15 otide derivatives with the ribose 29,39-hydroxyl groups in a chemically Various P2XR antagonists have shown efficacy in pain models. 43 For example, involvement of P2XRs has been explored in protected
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