Back to Journals » Journal of Experimental Pharmacology » Volume 10

Cannabinoids and agmatine as potential therapeutic alternatives for cisplatin-induced peripheral neuropathy

Authors Donertas B, Cengelli Unel C , Erol K 

Received 9 January 2018

Accepted for publication 14 April 2018

Published 22 June 2018 Volume 2018:10 Pages 19—28

DOI https://doi.org/10.2147/JEP.S162059

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Bal Lokeshwar



Basak Donertas,* Cigdem Cengelli Unel,* Kevser Erol

Department of Medical Pharmacology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey

*These authors contributed equally to this work

Abstract: Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has the potential to result in limiting and/or reducing the dose, decreasing the quality of life. Unfortunately, the mechanism for cisplatin-induced neuropathy has not been completely elucidated. Currently, available treatments for neuropathic pain (NP) are mostly symptomatic, insufficient and are often linked with several detrimental side effects; thus, effective treatments are needed. Cannabinoids and agmatine are endogenous modulators that are implicated in painful states. This review explains the cisplatin-induced neuropathy and antinociceptive effects of cannabinoids and agmatine in animal models of NP and their putative therapeutic potential in cisplatin-induced neuropathy and antinociceptive effects of cannabinoids and agmatine in animal models of NP and their putative therapeutic potential in cisplatin-induced neuropathy.

Keywords: agmatine, anandamide, cisplatin, neuropathy

Introduction

Cisplatin (cis-dichlorodiammineplatinum II) is the first agent of platinum drugs that is widely used as a first-line treatment for several solid and blood cancers.1 Platinum derivatives exert antitumor activity by reacting with the DNA, and they damage DNA by intra- and interstrand crosslinks, which then induce apoptotic cell death in dividing cells and cancer cells.2 They hardly cross the blood–brain barrier but have a high affinity to the peripheral nervous system.3 Despite its efficacy, cisplatin causes predominantly sensory axonal peripheral neuropathy (PN), which limits the dose delivered, reduces likelihood of an effective treatment and affects patients’ quality of life.4 The major symptoms of this condition are sensory loss, painful paresthesias, weakness, tremors, numbness, temperature sensitivity and hyperalgesia in a “stocking and glove” distribution.5 The symptoms may begin after the first dose or at the end of the therapy and may appear after weeks to several months even after the discontinuation of therapy, a process known as coasting phenomenon.4 Higher cumulative doses and long-lasting cisplatin treatment may also lead to chronic and irreversible PN.6 Approximately 60% of patients receiving a total cumulative cisplatin dose ranging from 225 to 500 mg/m2 suffer from peripheral nerve damage,7 and 10% of them experience treatment-emergent grade 3/4 neurotoxicity.8,9 The exact mechanism of cisplatin-induced PN has not been fully elucidated; however, various underlying mechanisms have been proposed.

Neuropathic pain (NP) is a chronic pain arising as a direct consequence of a lesion or disease affecting the somatosensory system in either the periphery or centrally.10 PN results from some type of damage to the peripheral nervous system caused by mechanical trauma, metabolic diseases, certain drugs and infections.11 Several mechanisms are thought to be responsible for NP, some of which consist of altered gene expression and changes in ion channels that cause ectopic activity in the peripheral nervous system. In addition, many gene regulations may also be changed in the central nervous system. Neuronal death and excessive synaptic interactivity lead to changes in both nociceptive and innocuous afferent inputs.11

Cisplatin has been found at higher levels in dorsal root ganglia (DRG) than in peripheral nerve or in the central nervous system in patients with cisplatin therapy.12,13 The severity of PN correlates with platinum levels in these cells.6,14 The presence of an abundant fenestrated capillary network and absence of an effective blood–brain barrier in the DRG15 allow platinum drugs to accumulate in the DRG with easy access to sensory neurons, explaining the main sensory symptoms in PN.16

Cisplatin could also affect the central nervous system and extensively cause cytotoxicity when injected directly into the brain.17 Cytoplasmic changes including deep invaginations between satellite cells and the neuronal surface and formations of vacuoli in satellite cells of DRG were also reported by cisplatin treatment.18 There are some limited evidence that cisplatin affects proinflammatory cytokine expression and causes some changes in immune signaling pathways. However, the results of these neuroinflammatory responses need to be clarified by further investigations.19 Copper transporter 1 and copper-transporting ATPases, expressed on the DRG membrane, are responsible for cellular uptake and accumulation of cisplatin in sensory neurons and contribute to the development of PN.20 After cisplatin enters into the cell, it directly binds to DNA and forms interstrand crosslinks and intrastrand adducts by changing the tertiary structure of DNA.20,21 Then, cell cycle kinetics is disrupted within the DRG, and these cells reenter into the cell cycle that results with apoptosis.22 The latter mechanism involves oxidative stress and mitochondrial dysfunction as a component of neuronal apoptosis.23 Cisplatin binds to mitochondrial DNA (mtDNA) and nuclear (n) DNA in the DRG.24 mtDNA does not have any DNA repair system; thus, platinum adducts cannot be removed from mtDNA. This causes perturbations in protein synthesis and mitochondrial respiratory chain reactions.24 Mitochondrial dysfunction and failure in energy metabolism of the cell lead to overproduction of reactive oxygen species and induce cellular oxidative stress. Moreover, cisplatin causes mitochondrial release of cytochrome c and caspases promoting apoptosis via the mitochondrial intrinsic pathway.23 Cisplatin also increases the activity of p53 and p38 proteins and extracellular signal-regulated kinase (ERK) 1/2 signaling pathways.25 In addition, it may increase the expression levels of transient receptor potential vanilloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential melastatin 8 (TRPM8) in cultured DRG cells.26,27

Many agents have been proposed to manage chemotherapy-induced NP such as vitamin E, glutamine, α-lipoic acid, glutathione, calcium–magnesium, acetyl cysteine, acetyl-l-carnitine, amifostine, diethyldithiocarbamate and glutathione. However, none of these agents has been proven effective.28 Some agents such as caffeic acid phenethyl ester,29 pifithrin-μ,30 APX2009,31 mesenchymal stem cells,32 Org 2766, glutathione, amifostine and various neurotrophic growth factors28 were suggested to prevent or limit the cisplatin neurotoxicity, which are still under investigation. Therefore, there is still a great need for effective treatments.

In this review, the studies demonstrating the antinociceptive effects of endogenous modulators cannabinoids and agmatine in animal models of NP, as well as the mechanisms of action related to such effects, are discussed. We present the evidence to support the potential of cannabinoids and agmatine as adjuvants/monotherapy for cisplatin-induced PN.

Cannabinoids and NP

Cannabinoids represent a wide range of endogenous or exogenous compounds that include phytocannabinoids, the natural compounds found in plants of the genus Cannabis; endogenous cannabinoids and synthetic ligands.33 Cannabis has an ancient medicinal history, but the potential value of the cannabinoids for medicinal purposes arose from the discovery of cannabinoid receptors and their endogenous ligands.3335 Investigations into the chemistry of Cannabis began in the mid-19th century, and cannabinol, cannabidiol (CBD) and the main active compound delta-9-tetrahydrocannabinol (Δ-9-THC) were isolated, respectively.33,36 Another cornerstone in cannabinoid research was the identification of cannabinoid receptor system between 1980 and 2000s, and then, this system was named as endocannabinoid system.36

There has been an increasing interest in the therapeutic potential of cannabinoids for the treatment of many disorders and symptoms.35 However, cognitive–behavioral effects and widely illicit use of cannabinoids in the world have created political and regulatory obstacles, and they were included as controlled drugs in the United Nations Single Convention on Narcotic Drugs, and their use is illegal in most countries.37

Cannabinoids produce their actions through the activation of G-protein-coupled cannabinoid receptors, CB1 and CB2.32,36 Activation of both CB1 and CB2 receptors inhibits adenylate cyclase activity, and CB1 receptor activation can also inhibit type 5-HT3 ion channels; modulate the production of nitric oxide (NO); alter conductance of calcium, potassium or sodium channel and activate the Na+/H+ exchanger, the pathways that have been implicated in pain transduction and perception.32,38,39 CB1 receptors are found mainly in the central nervous system, and CB2 receptors are primarily localized to cells of the immune system.32 More significantly for the purposes of the present review, CB1 receptors are those present in sensory neurons (DRG and trigeminal ganglia), as well as defense cells such as macrophages, mast cells and keratinocytes.40 Few CB2 receptors are located in the brain, spinal cord and DRG, but they increase in response to peripheral nerve damage. They modulate central neuroimmune interactions and interfere with inflammatory hyperalgesia.41

Anandamide (N-arachidonoylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) are the main endogenous ligands of cannabinoid receptors derived from the membrane-localized phospholipid precursors and are recruited during tissue injury to provide a first response to nociceptive signals.34,42 Besides cannabinoid receptors, they have been also shown to exert several effects via other targets, such as transient receptor potential (TRP) channels; orphan G-coupled receptors such as GPR55, GPR92, GPR18 and GPR119; T-type calcium channels; glycine receptors and GABAA receptor.38

AEA is synthesized from the phosphatidylethanolamine, an abundant lipid present in the cell membrane, by N-acyltransferase and phospholipase D, and it is mainly degraded by fatty acid amide hydrolase (FAAH).43 2-AG is synthesized from diacylglycerol by diacylglycerol lipase and is primarily metabolized by monoacylglycerol lipase (MGL).43

Antinociceptive effects of cannabinoids in animal models of NP

Studies evaluating the presence of hyperalgesia following blockade of CB1 receptors provided early physiological support for the hypothesis that endocannabinoids suppress pain.39 Since then many studies have been performed to investigate the antinociceptive effects of cannabinoids and their modulation in acute, inflammatory and NP models. The discovery of endocannabinoid system, as one of the neuromodulatory system involved in the pathophysiology of NP, raised the interest for the development of new therapeutic strategies.32,44,45 Endocannabinoid system is expressed highly in neurons and immune cells that are crucial for the development of NP,4648 and there is also evidence available stating that endocannabinoid levels are altered in several regions of ascending and descending pain pathways in NP states.49 Furthermore, endocannabinoids have been shown to interact with other receptor systems, including GABA, serotonin, adrenergic and opioid receptors, which are involved in the antinociceptive effects of common NP medications.32,38,45,50 Based on the existing data, new pharmacological agents have been investigated in various animal models of NP through the manipulation of cannabinoid receptors and transporters or blocking enzymes involved in the endocannabinoid degradation (Table 1).32,38,44,45

Table 1 Substances modulating the endocannabinoid system in NP

Abbreviations: AEA, N-arachidonoylethanolamine; CB, cannabinoid; CBD, cannabidiol; FAAH, fatty-acid amide hydrolase; MGL, monoacylglycerol lipase; NP, neuropathic pain; THC, tetrahydrocannabinol.

Cannabinoid receptor agonists have shown antinociceptive properties in a variety of NP models. They have been shown to alleviate hyperalgesia in peripheral nerve injury-induced,5160 chemotherapy-induced,6168 diabetes-induced6974 and antiretroviral-induced75 neuropathy models. The antihyperalgesic effect of cannabinoids was suggested to be mediated through cannabinoid receptors,51,53,68,7577 interacting with spinal mGlu5 receptors,78 5-HT1A receptors,79 posterior inhibition of p38 MAPK/NF-κB activation and cytokine release,68 GPR55 activation75 and stimulating endogenous norepinephrine release.80

Inflammation has also been shown to be involved in the development of NP,81 and cannabinoid agonists may abolish the increased levels of mediators known to be involved in NP, such as prostaglandin E2 (PGE2), NO and the neuronal NO synthase.54 All these mediators may lead to attenuate the early production of spinal proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α.62 SR141716 (rimonabant), an antagonist/inverse agonist of CB1 receptor, has also exerted antihyperalgesic activity in the chronic constriction injury model by reducing the levels of TNF-α, PGE2, lipoperoxide and NO45 in diabetic neuropathy.82,83

Cannabinoid receptor agonists have been suggested to have good analgesic efficacy in animal models of NP, but their use is limited by motor and psychotropic side effects. It has been proposed that these side effects might be overcome by using agents that indirectly activate the endocannabinoid system.84,85 Substances inhibiting the reuptake of endocannabinoids8688 or inhibiting the FAAH and MGL, degradation enzymes of the two major endocannabinoids – anandamide or 2-AG, respectively, have found to be effective in the attenuation of neuropathy.84,8995 On the other hand, selective FAAH and MGL inhibitors were suggested to have a better therapeutic window than cannabinoid agonists, but they exerted lesser efficacy in these pain models. For instance, the FAAH inhibitor PF04457845 has not progressed through human chronic pain studies because of poor efficacy.96 However, dual inhibitor of FAAH and MGL or a combination of FAAH inhibitor with a low dose of the MAGL inhibitor had greater anti-allodynic efficacy than selective FAAH or MGL inhibitors plus a greater therapeutic window than a cannabinoid receptor agonist.84,85,94

The abovementioned data indicate that endocannabinoids modulate pain under physiological conditions, and the high amount of preclinical evidence reports the antinociceptive effects of cannabinoids in NP. All these observations have led clinicians to start clinical trials using cannabinoids for the treatment of chronic pain.38,97 For instance, Sativex (nabiximols) is prescribed for the symptomatic relief of NP in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer,98 and nabiximols has been approved as a botanical drug in the UK in 2010 as a mouth spray to alleviate NP, spasticity, overactive bladder and other symptoms associated with multiple sclerosis.99,100

Antinociceptive effects of cannabinoids in cisplatin-induced NP

Considering their antinociceptive effects in NP, cannabinoids are also evaluated in the animal model of cisplatin-induced neuropathy. Cisplatin has been shown to alter endocannabinoid tone,95 and inhibition of endocannabinoid hydrolysis by FAAH and MGL inhibitors95 or administration of cannabinoid agonists produced antinociceptive effects.63,70 AM1710, a cannabilactone CB2 selective agonist, produced CB2-mediated suppressions of mechanical and cold allodynia induced by cisplatin.101 Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds and decreased evoked responses to mechanical stimuli, which were mediated primarily by CB1 receptors.102 CBD and Δ-9-THC attenuated cisplatin-induced tactile allodynia, but they could not prevent cisplatin-induced neuropathy when administered prophylactically.66 Co-administration of JZL184, an inhibitor of endocannabinoid 2-arachidonoyl-sn-glycerol, with cisplatin blocked mechanical hyperalgesia, which might result from downstream activation of CB1 receptors.103 In our studies, concurrent,104,105 but not acute,106 administration of anandamide or agmatine attenuated neuropathy. Cisplatin also had concentration-dependent neurotoxic effects on DRG in vitro, and a high concentration of anandamide attenuated cisplatin neurotoxicity.106

Agmatine: history and pharmacological importance

Agmatine, 4-aminobutyl guanidine, is an endogenous amine that was first discovered and purified from herring sperm ~100 years ago by Kossel.107 It is widely distributed in many tissues including brain, stomach, intestine and aorta.108 Agmatine is synthesized following decarboxylation of l-arginine by arginine decarboxylase.109 Agmatine was thought to have an important role in arginine and polyamine metabolism, and at first was only attributed to bacteria110,111 and plants.112 However, in 1994, agmatine was purified from bovine brain as a clonidine-displacing substance and called endogenous ligand for the imidazoline receptors.113 It is expressed in the central nervous system and meets most of the criteria of a neurotransmitter/neuromodulator.111 Agmatine antagonizes N-methyl-d-aspartic acid (NMDA) receptors, inhibits competitively all isoforms of nitric oxide synthase (NOS)110 and binds to α2-adrenoceptors, imidazoline receptors as well as 5-HT3 and nicotinic acetylcholine receptors with moderate affinity.109,111,113 It has several biological functions such as cognitive, anxiolytic, antidepressant, antiproliferative properties against tumor cells and neuroprotective properties.114116 Agmatine also modulates morphine dependence and tolerance.117

Antinociceptive effects of agmatine in animal models of NP

Agmatine has produced antihyperalgesic and antiallodynic effects in animal models of chronic neuropathic and inflammatory pain. Intrathecal injection of agmatine increased dose-dependently morphine analgesia and potentiated acutely delta opioid receptor-mediated analgesia.118 Its peripheral administration was shown to enhance the antinociceptive effect of co-administered morphine through α2-adrenoceptor-mediated mechanism.119 Agmatine antagonized some hyperalgesic states;119,120 reversed inflammation-, spinal cord injury- and nerve injury-induced pain121 and attenuated the streptozotocin-induced122 and sciatic nerve ligation-induced NP.123

In diabetic neuropathy, l-arginine supplementation has been shown to prevent the development of mechanical hyperalgesia and tactile and thermal allodynia with concomitant reduction of NO.124 It was also shown that spinal agmatine produced antiallodynic and antihyperalgesic effects in diabetic neuropathy involving the imidazoline receptors.125 In diabetes mellitus (DM), oxidative and also nitrosative stress induced by persistent hyperglycemia is considered as one of the pivotal contributors in DM-associated neural dysfunction.126 Elevated oxidative stress leads to vascular dysfunction with ensuing endoneurial hypoxia, which causes impaired motor and sensory nerve functions.127 In addition, l-arginine deficiency was also reported in streptozotocin-induced diabetes in rats.128 NO, agmatine and glutamate share common NMDA receptor-mediated effects in the central nervous system. These underlying mechanisms may be responsible for the antinociceptive effects of agmatine in diabetic neuropathy.

Traumatic nerve injury also induces chronic pain and may trigger common, secondary pathological cascades, including activation of NMDA receptor,129 AMPA/kainate receptors130 and NOS.131 NMDA receptor activation increases intracellular Ca+2, which activates NOS to produce NO from l-arginine. NMDA receptors are known to have an important role in chronic pain processing from peripheral nerve injury. In sciatic nerve ligation-induced NP model, agmatine attenuated NP,118,122 which may involve the reduction of NO levels and noradrenergic activity in the brain.118 These beneficial effects of agmatine may partly result from the participation of noradrenergic neurons in the locus coeruleus involved in the development and/or maintenance of allodynia and hyperalgesia in the setting of peripheral nerve injury.132 Agmatine can bind to α2 and imidazoline (1) receptors. An imbalance of supraspinal inhibition and facilitation was suggested to play a role in neuropathic hypersensitivity.132 The locus coeruleus was reported to contribute to bidirectional modulation of pain.133 It was shown that noradrenergic locus coeruleus lesions inhibited the development of allodynia and hyperalgesia and noradrenergic reuptake inhibitors decreased NP.134 Although the locus coeruleus seems as a pain inhibitory structure,133,135 there are some results indicating that it could participate in the facilitation of NP. The coeruleospinal noradrenergic fibers were suggested to be involved in descending inhibition of spinal pain transmission.136 Agmatine was demonstrated to reduce norepinephrine and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) levels in the brainstem and lead to increased pain threshold in NP.123 The decreased central noradrenergic activity by agmatine via presynaptic α2-adrenoceptor activation was suggested to involve in the relief of NP.123 Additionally, it was also reported that α2-adrenoceptor activation leads to release of acetylcholine and mechanical hyperalgesia is inhibited via muscarinic receptors at spinal levels.137

The antihyperalgesic effect of agmatine probably involves spinal imidazoline (1) receptors. It was reported that an imidazoline (1) receptor antagonist could reduce the antiallodynic and antihyperalgesic activities of agmatine in diabetic NP.125 In addition, agmatine has also an antiallodynic effect in both animal models of NP with spinal nerve ligation and diabetes.122

In regard to all underlying mechanisms of NP, agmatine can partly overcome different kinds of neuropathies considering its NMDA receptor antagonist, NOS inhibitory and anti-inflammatory activities.121 Neuronal injury and chronic pain can trigger several pathological cascades including stimulations of NMDA receptors and NOS.129 Agmatine was shown to inhibit NMDA receptors, NMDA-mediated Ca2 currents and also all isoforms of NOS, most potently inducible forms.110,138 Recently, we also demonstrated that agmatine could prevent cisplatin-induced mechanical allodynia and degeneration of DRG cells and sciatic nerves. Our results showed that l-NAME did not significantly potentiate the antiallodynic and neuroprotective effects of agmatine.139 It was demonstrated that NOS inhibitors and NMDA receptor antagonists could increase the release of 5-HT by activating tryptophan hydroxylase.140 It can be thought that the increase in serotonin could contribute the antinociceptive activity of agmatine.

Since microglial and astrocytic cells release neurotrophic factors that have proinflammatory and neuroprotective effects, it was also suggested that macrophages, activated microglia and infiltrated monocytes have a major role in neuroinflammation.141

It was suggested that agmatine might increase the anti-inflammatory M2 macrophage properties without enhancing cell numbers.142 This can also contribute to its activity against neuropathies, considering the proinflammatory M1 and anti-inflammatory M2 macrophages-induced promotion of axonal regeneration after neuronal injury.141,143

Furthermore, agmatine is widely distributed in several brain regions including hippocampus and co-localized with sigma receptors.108 Sigma receptors were also found in sciatic nerves,144 and especially, sigma 1 receptors had a role to modulate NP.145 Additionally, there are some reports to suggest the elevation of hippocampal TNF-α levels in NP.146 The agonists of sigma 1 and sigma 2 receptors were found to stimulate the production of TNF-α, and agmatine decreased the levels of TNF-α, suggesting to block these receptors in NP-induced rats.147

Therefore, the antinociception caused by agmatine may involve opioidergic, serotonergic, α2-adrenergic, imidazoline148 and opioidergic sigma receptors,147 which were recently reported to play an important role in antinociceptive activity of agmatine in NP.143 These predictions need further investigations.

Conclusion

NP arises through multiple and complex mechanisms. The use of animal models helped to understand the pathophysiological mechanisms and to better define the treatment targets. Many scientific investigations on the effects of cannabinoids and agmatine on NP are now available considering endocannabinoid system’s involvement in NP and agmatine’s multiple targets, which are also implicated in NP, and give rise to new therapeutic opportunities. Cannabinoid ligands could open future perspectives for NP management, but their potential harms should be outweighed. At this point, substances that indirectly activate the endocannabinoid system with inhibition of the reuptake of endocannabinoids or degradation enzymes might be promising with less side effects. Furthermore, experimental studies indicate that agmatine gives great promise for the development of an improved treatment of this common disease. At the same time, agmatine has been shown to have a good safety profile with no effect on behavior, locomotion, or cardiovascular functions in naive animals.149

Acknowledgment

The authors would like to thank Maithili Jais for the language editing.

Disclosure

The authors report no conflicts of interest in this work.

References

1.

Tsang RY, Al-Fayea T, Au HJ. Cisplatin overdose: toxicities and management. Drug Safety. 2009;32(12):1109–1122.

2.

Huang H, Zhu L, Reid BR, Drobny GP, Hopkins PB. Solution structure of a cisplatin-induced DNA interstrand cross-link. Science. 1995;270(5243):1842–1845.

3.

Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249(1):9–17.

4.

Starobova H, Vetter I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci. 2017;10:174.

5.

Amptoulach S, Tsavaris N. Neurotoxicity caused by the treatment with platinum analogues. Chemother Res Pract. 2011;2011:843019.

6.

Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol. 1992;10(5):795–803.

7.

Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol. 2012;82(1):51–77.

8.

Sutton G, Brunetto VL, Kilgore L, et al. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: a Gynecologic Oncology Group Study. Gynecol Oncol. 2000;79(2):147–153.

9.

Gatzemeier U, von Pawel J, Gottfried M, et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000;18(19):3390–3399.

10.

Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807–819.

11.

Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32.

12.

Thompson SW, Davis LE, Kornfeld M, Hilgers RD, Standefer JC. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer. 1984;54(7):1269–1275.

13.

Krarup-Hansen A, Rietz B, Krarup C, Heydorn K, Rorth M, Schmalbruch H. Histology and platinum content of sensory ganglia and sural nerves in patients treated with cisplatin and carboplatin: an autopsy study. Neuropathol Appl Neurobiol. 1999;25(1):29–40.

14.

Dzagnidze A, Katsarava Z, Makhalova J, et al. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy. J Neurosci. 2007;27(35):9451–9457.

15.

Allen DT, Kiernan JA. Permeation of proteins from the blood into peripheral nerves and ganglia. Neuroscience. 1994;59(3):755–764.

16.

Kanat O, Ertas H, Caner B. Platinum-induced neurotoxicity: a review of possible mechanisms. World J Clin Oncol. 2017;8(4):329–335.

17.

Namikawa K, Asakura M, Minami T, Okazaki Y, Kadota E, Hashimoto S. Toxicity of cisplatin to the central nervous system of male rabbits. Biol Trace Elem Res. 2000;74(3):223–235.

18.

Cece R, Petruccioli MG, Pizzini G, Cavaletti G, Tredici G. Ultrastructural aspects of DRG satellite cell involvement in experimental cisplatin neuronopathy. J Submicrosc Cytol Pathol. 1995;27(4):417–425.

19.

Lees JG, Makker PG, Tonkin RS, et al. Immune-mediated processes implicated in chemotherapy-induced peripheral neuropathy. Eur J Cancer. 2017;73:22–29.

20.

Cavaletti G, Ceresa C, Nicolini G, Marmiroli P. Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity. Anticancer Res. 2014;34(1):483–486.

21.

McDonald ES, Randon KR, Knight A, Windebank AJ. Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis. 2005;18(2):305–313.

22.

Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest. 1998;101(12):2842–2850.

23.

Canta A, Pozzi E, Carozzi VA. Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). Toxics. 2015;3(2):198–223.

24.

Podratz JL, Knight AM, Ta LE, et al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons. Neurobiol Dis. 2011;41(3):661–668.

25.

Scuteri A, Galimberti A, Maggioni D, et al. Role of MAPKs in platinum-induced neuronal apoptosis. Neurotoxicology. 2009;30(2):312–319.

26.

Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral neuropathy: what do we know about mechanisms? Neurosci Lett. 2015;596:90–107.

27.

Ta LE, Bieber AJ, Carlton SM, Loprinzi CL, Low PA, Windebank AJ. Transient receptor potential vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. Mol Pain. 2010;6:15.

28.

Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;31(3):Cd005228.

29.

Ferreira RS, Dos Santos NAG, Martins NM, Fernandes LS, Dos Santos AC. Caffeic acid phenethyl ester (CAPE) protects PC12 cells from cisplatin-induced neurotoxicity by activating the NGF-signaling pathway. Neurotox Res. Epub 2017 Dec 19.

30.

Maj MA, Ma J, Krukowski KN, Kavelaars A, Heijnen CJ. Inhibition of mitochondrial p53 accumulation by PFT-mu prevents cisplatin-induced peripheral neuropathy. Front Mol Neurosci. 2017;10:108.

31.

Kelley MR, Wikel JH, Guo C, et al. Identification and characterization of new chemical entities targeting apurinic/apyrimidinic endonuclease 1 for the prevention of chemotherapy-induced peripheral neuropathy. J Pharmacol Exp Ther. 2016;359(2):300–309.

32.

Scuteri A, Ravasi M, Monfrini M, et al. Human mesenchymal stem cells protect dorsal root ganglia from the neurotoxic effect of cisplatin. Anticancer Res. 2015;35(10):5383–5389.

33.

Mechoulam R, Hanus LO, Pertwee R, Howlett AC. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci. 2014;15(11):757–764.

34.

Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462.

35.

Grotenhermen F, Muller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int. 2012;109(29–30):495–501.

36.

Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2(6):241–254.

37.

United Nations. Single Convention on Narcotic Drugs 1961. New York, NY: United Nations; 1962.

38.

Luongo L, Starowicz K, Maione S, Di Marzo V. Allodynia lowering induced by cannabinoids and endocannabinoids (ALICE). Pharmacol Res. 2017;119:272–277.

39.

Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009;8(6):403–421.

40.

Piomelli D, Sasso O. Peripheral gating of pain signals by endogenous analgesic lipids. Nat Neurosci. 2014;17(2):164–174.

41.

Whiteside GT, Lee GP, Valenzano KJ. The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr Med Chem. 2007;14(8):917–936.

42.

Hill KP, Palastro MD, Johnson B, Ditre JW. Cannabis and pain: a clinical review. Cannabis Cannabinoid Res. 2017;2(1):96–104.

43.

Maldonado R, Banos JE, Cabanero D. The endocannabinoid system and neuropathic pain. Pain. 2016;157(suppl 1):S23–S32.

44.

Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6(4):713–737.

45.

Costa B, Trovato AE, Colleoni M, Giagnoni G, Zarini E, Croci T. Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve. Pain. 2005;116(1–2):52–61.

46.

Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids. 2002;66(2–3):243–256.

47.

Mitrirattanakul S, Ramakul N, Guerrero AV, et al. Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain. 2006;126(1–3):102–114.

48.

Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O’Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003;17(12):2750–2754.

49.

Jhaveri MD, Richardson D, Chapman V. Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. Br J Pharmacol. 2007;152(5):624–632.

50.

Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2017;125(5):1638–1652.

51.

Liang YC, Huang CC, Hsu KS. The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain. Neuropharmacology. 2007;53(1):169–177.

52.

Guindon J, Desroches J, Dani M, Beaulieu P. Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain. Eur J Pharmacol. 2007;568(1–3):173–176.

53.

Bridges D, Ahmad K, Rice ASC. The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol. 2001;133(4):586–594.

54.

Costa B, Colleoni M, Conti S, et al. Repeated treatment with the synthetic cannabinoid WIN 55,212-2 reduces both hyperalgesia and production of pronociceptive mediators in a rat model of neuropathic pain. Br J Pharmacol. 2004;141(1):4–8.

55.

Lever IJ, Pheby TM, Rice AS. Continuous infusion of the cannabinoid WIN 55,212-2 to the site of a peripheral nerve injury reduces mechanical and cold hypersensitivity. Br J Pharmacol. 2007;151(2):292–302.

56.

Li AL, Carey LM, Mackie K, Hohmann AG. Cannabinoid CB2 agonist GW405833 suppresses inflammatory and neuropathic pain through a CB1 mechanism that is independent of CB2 receptors in mice. J Pharmacol Exp Ther. 2017;362(2):296–305.

57.

Casey SL, Atwal N, Vaughan CW. Cannabis constituent synergy in a mouse neuropathic pain model. Pain. 2017;158(12):2452–2460.

58.

Costa B, Trovato AE, Comelli F, Giagnoni G, Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2007;556(1–3):75–83.

59.

Kazantzis NP, Casey SL, Seow PW, Mitchell VA, Vaughan CW. Opioid and cannabinoid synergy in a mouse neuropathic pain model. Br J Pharmacol. 2016;173(16):2521–2531.

60.

Gunduz O, Topuz RD, Karadag CH, Ulugol A. Analysis of the anti-allodynic effects of combination of a synthetic cannabinoid and a selective noradrenaline re-uptake inhibitor in nerve injury-induced neuropathic mice. Eur J Pain. 2016;20(3):465–471.

61.

Pascual D, Goicoechea C, Suardiaz M, Martin MI. A cannabinoid agonist, WIN 55,212-2, reduces neuropathic nociception induced by paclitaxel in rats. Pain. 2005;118(1–2):23–34.

62.

Burgos E, Gomez-Nicola D, Pascual D, Martin MI, Nieto-Sampedro M, Goicoechea C. Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells. Eur J Pharmacol. 2012;682(1–3):62–72.

63.

Vera G, Chiarlone A, Cabezos PA, Pascual D, Martin MI, Abalo R. WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. Life Sci. 2007;81(6):468–479.

64.

Rahn EJ, Deng L, Thakur GA, et al. Prophylactic cannabinoid administration blocks the development of paclitaxel-induced neuropathic nociception during analgesic treatment and following cessation of drug delivery. Mol Pain. 2014;10:27.

65.

Deng L, Guindon J, Cornett BL, Makriyannis A, Mackie K, Hohmann AG. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 2015;77(5):475–487.

66.

Harris HM, Sufka KJ, Gul W, ElSohly MA. Effects of delta-9-tetrahydrocannabinol and cannabidiol on cisplatin-induced neuropathy in mice. Planta Med. 2016;82(13):1169–1172.

67.

Ward SJ, Ramirez MD, Neelakantan H, Walker EA. Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice. Anesth Analg. 2011;113(4):947–950.

68.

Segat GC, Manjavachi MN, Matias DO, et al. Antiallodynic effect of beta-caryophyllene on paclitaxel-induced peripheral neuropathy in mice. Neuropharmacology. 2017;125:207–219.

69.

Ulugol A, Karadag HC, Ipci Y, Tamer M, Dokmeci I. The effect of WIN 55,212-2, a cannabinoid agonist, on tactile allodynia in diabetic rats. Neurosci Lett. 2004;371(2–3):167–170.

70.

Vera G, Cabezos PA, Martin MI, Abalo R. Characterization of cannabinoid-induced relief of neuropathic pain in a rat model of cisplatin-induced neuropathy. Pharmacol Biochem Behav. 2013;105:205–212.

71.

Ikeda H, Ikegami M, Kai M, Ohsawa M, Kamei J. Activation of spinal cannabinoid CB2 receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice. Neuroscience. 2013;250:446–454.

72.

Toth CC, Jedrzejewski NM, Ellis CL, Frey WH. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Mol Pain. 2010;6:16.

73.

Jahanabadi S, Hadian MR, Shamsaee J, et al. The effect of spinally administered WIN 55,212-2, a cannabinoid agonist, on thermal pain sensitivity in diabetic rats. Iran J Basic Med Sci. 2016;19(4):394–401.

74.

Schreiber AK, Neufeld M, Jesus CH, Cunha JM. Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats. Neuropharmacology. 2012;63(8):1286–1297.

75.

Munawar N, Oriowo MA, Masocha W. Antihyperalgesic activities of endocannabinoids in a mouse model of antiretroviral-induced neuropathic pain. Front Pharmacol. 2017;8:136.

76.

Hama A, Sagen J. Activation of spinal and supraspinal cannabinoid-1 receptors leads to antinociception in a rat model of neuropathic spinal cord injury pain. Brain Res. 2011;1412:44–54.

77.

Ahmed MM, Rajpal S, Sweeney C, et al. Cannabinoid subtype-2 receptors modulate the antihyperalgesic effect of WIN 55,212-2 in rats with neuropathic spinal cord injury pain. Spine J. 2010;10(12):1049–1054.

78.

Hama AT, Urban MO. Antihyperalgesic effect of the cannabinoid agonist WIN55,212-2 is mediated through an interaction with spinal metabotropic glutamate-5 receptors in rats. Neurosci Lett. 2004;358(1):21–24.

79.

Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol. 2014;171(3):636–645.

80.

Romero TR, Resende LC, Guzzo LS, Duarte ID. CB1 and CB2 cannabinoid receptor agonists induce peripheral antinociception by activation of the endogenous noradrenergic system. Anesth Analg. 2013;116(2):463–472.

81.

Schomberg D, Ahmed M, Miranpuri G, Olson J, Resnick DK. Neuropathic pain: role of inflammation, immune response, and ion channel activity in central injury mechanisms. Ann Neurosci. 2012;19(3):125–132.

82.

Comelli F, Bettoni I, Colombo A, Fumagalli P, Giagnoni G, Costa B. Rimonabant, a cannabinoid CB1 receptor antagonist, attenuates mechanical allodynia and counteracts oxidative stress and nerve growth factor deficit in diabetic mice. Eur J Pharmacol. 2010;637(1–3):62–69.

83.

Liu WJ, Jin HY, Park JH, Baek HS, Park TS. Effect of rimonabant, the cannabinoid CB1 receptor antagonist, on peripheral nerve in streptozotocin-induced diabetic rat. Eur J Pharmacol. 2010;637(1–3):70–76.

84.

Adamson Barnes NS, Mitchell VA, Kazantzis NP, Vaughan CW. Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model. Br J Pharmacol. 2016;173(1):77–87.

85.

Anderson WB, Gould MJ, Torres RD, Mitchell VA, Vaughan CW. Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model. Neuropharmacology. 2014;81:224–230.

86.

Costa B, Siniscalco D, Trovato AE, et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br J Pharmacol. 2006;148(7):1022–1032.

87.

Mitchell VA, Greenwood R, Jayamanne A, Vaughan CW. Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models. Clin Exp Pharmacol Physiol. 2007;34(11):1186–1190.

88.

La Rana G, Russo R, Campolongo P, et al. Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J Pharmacol Exp Ther. 2006;317(3):1365–1371.

89.

Jhaveri MD, Richardson D, Kendall DA, Barrett DA, Chapman V. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J Neurosci. 2006;26(51):13318–13327.

90.

Russo R, Loverme J, La Rana G, et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3’-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J Pharmacol Exp Ther. 2007;322(1):236–242.

91.

Maione S, De Petrocellis L, de Novellis V, et al. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br J Pharmacol. 2007;150(6):766–781.

92.

Clapper JR, Moreno-Sanz G, Russo R, et al. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat Neurosci. 2010;13(10):1265–1270.

93.

Kinsey SG, Long JZ, Cravatt BF, Lichtman AH. Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors produce anti-allodynic effects in mice through distinct cannabinoid receptor mechanisms. J Pain. 2010;11(12):1420–1428.

94.

Ghosh S, Kinsey SG, Liu QS, et al. Full fatty acid amide hydrolase inhibition combined with partial monoacylglycerol lipase inhibition: augmented and sustained antinociceptive effects with reduced cannabimimetic side effects in mice. J Pharmacol Exp Ther. 2015;354(2):111–120.

95.

Guindon J, Lai Y, Takacs SM, Bradshaw HB, Hohmann AG. Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacol Res. 2013;67(1):94–109.

96.

Huggins JP, Smart TS, Langman S, Taylor L, Young T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain. 2012;153(9):1837–1846.

97.

Mücke MPT, Radbruch L, Petzke F, Häuser W. Cannabinoids for chronic neuropathic pain. Cochrane Database Syst Rev. 2016;(5):CD012182.

98.

Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol. 2009;156(3):397–411.

99.

Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex(R) (nabiximols). Mult Scler. 2012;18(2):219–228.

100.

Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage. 2013;46(2):207–218.

101.

Deng L, Guindon J, Vemuri VK, et al. The maintenance of cisplatin- and paclitaxel-induced mechanical and cold allodynia is suppressed by cannabinoid CB(2) receptor activation and independent of CXCR4 signaling in models of chemotherapy-induced peripheral neuropathy. Mol Pain. 2012;8:71.

102.

Uhelski ML, Khasabova IA, Simone DA. Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy. J Neurophysiol. 2015;113(5):1501–1510.

103.

Khasabova IA, Yao X, Paz J, et al. JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. Pharmacol Res. 2014;90:67–75.

104.

Cengelli Unel C, Aydin S, Donertas B, et al. Effects of chronic agmatine administration on cisplatin induced neuropathy in rats. Anatomy. 2017;11(suppl 1):S1–S86.

105.

Donertas B, Aydin S, Cengelli Unel C, et al. Effects of chronic anandamide administration on cisplatin induced neuropathy in rats. Anatomy. 2017;11(suppl 1):S1–S86.

106.

Kaygisiz BDB, Aydin S, Cengelli C, Yildirim E, Ulupinar E, Erol K. Effects of anandamide on cisplatin-induced neuropathy and neurotoxicity. 7th European Congress of Pharmacology, Congress Book P108. Vol. 26–30. İstanbul; 2016:385.

107.

Kossel A. Über das agmatin. Zeitschrift für Physiologische Chemie. 1911;66:257–261.

108.

Otake K, Ruggiero DA, Regunathan S, Wang H, Milner TA, Reis DJ. Regional localization of agmatine in the rat brain: an immunocytochemical study. Brain Res. 1998;787(1):1–14.

109.

Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994;263(5149):966–969.

110.

Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J. 1996;316(pt 1):247–249.

111.

Reis DJ, Regunathan S. Agmatine: an endogenous ligand at imidazoline receptors is a novel neurotransmitter. Ann N Y Acad Sci. 1999;881:65–80.

112.

Demady DR, Jianmongkol S, Vuletich JL, Bender AT, Osawa Y. Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme. Mol Pharmacol. 2001;59(1):24–29.

113.

Raasch W, Schäfer U, Chun J, Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol. 2001;133(6):755–780.

114.

McKay BE, Lado WE, Martin LJ, Galic MA, Fournier NM. Learning and memory in agmatine-treated rats. Pharmacol Biochem Behav. 2002;72(3):551–557.

115.

Lavinsky D, Arteni NS, Netto CA. Agmatine induces anxiolysis in the elevated plus maze task in adult rats. Behav Brain Res. 2003;141(1):19–24.

116.

Zhu MY, Wang WP, Bissette G. Neuroprotective effects of agmatine against cell damage caused by glucocorticoids in cultured rat hippocampal neurons. Neuroscience. 2006;141(4):2019–2027.

117.

Wu N, Su RB, Li J. Agmatine and imidazoline receptors: their role in opioid analgesia, tolerance and dependence. Cell Mol Neurobiol. 2008;28(5):629–641.

118.

Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur J Pharmacol. 1996;296(1):17–22.

119.

Yesilyurt O, Uzbay IT. Agmatine potentiates the analgesic effect of morphine by an alpha(2)-adrenoceptor-mediated mechanism in mice. Neuropsychopharmacology. 2001;25(1):98–103.

120.

Onal A, Soykan N. Agmatine produces antinociception in tonic pain in mice. Pharmacol Biochem Behav. 2001;69(1–2):93–97.

121.

Fairbanks CA, Schreiber KL, Brewer KL, et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A. 2000;97(19):10584–10589.

122.

Karadag HC, Ulugol A, Tamer M, Ipci Y, Dokmeci I. Systemic agmatine attenuates tactile allodynia in two experimental neuropathic pain models in rats. Neurosci Lett. 2003;339(1):88–90.

123.

Onal A, Delen Y, Ulker S, Soykan N. Agmatine attenuates neuropathic pain in rats: possible mediation of nitric oxide and noradrenergic activity in the brainstem and cerebellum. Life Sci. 2003;73(4):413–428.

124.

Rondon LJ, Farges MC, Davin N, et al. L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration. Eur J Nutr. Epub 2017 Jul 19.

125.

Courteix C, Privat AM, Pelissier T, Hernandez A, Eschalier A, Fialip J. Agmatine induces antihyperalgesic effects in diabetic rats and a superadditive interaction with R(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid, a N-methyl-D-aspartate-receptor antagonist. J Pharmacol Exp Ther. 2007;322(3):1237–1245.

126.

Stavniichuk R, Shevalye H, Lupachyk S, et al. Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2014;30(8):669–678.

127.

Kasznicki J, Kosmalski M, Sliwinska A, et al. Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy. Mol Biol Rep. 2012;39(9):8669–8678.

128.

Pieper GM, Dondlinger LA. Plasma and vascular tissue arginine are decreased in diabetes: acute arginine supplementation restores endothelium-dependent relaxation by augmenting cGMP production. J Pharmacol Exp Ther. 1997;283(2):684–691.

129.

Haghighi SS, Johnson GC, de Vergel CF, Vergel Rivas BJ. Pretreatment with NMDA receptor antagonist MK801 improves neurophysiological outcome after an acute spinal cord injury. Neurol Res. 1996;18(6):509–515.

130.

Grossman SD, Wolfe BB, Yasuda RP, Wrathall JR. Alterations in AMPA receptor subunit expression after experimental spinal cord contusion injury. J Neurosci. 1999;19(14):5711–5720.

131.

Hamada Y, Ikata T, Katoh S, et al. Roles of nitric oxide in compression injury of rat spinal cord. Free Radic Biol Med. 1996;20(1):1–9.

132.

Brightwell JJ, Taylor BK. Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience. 2009;160(1):174–185.

133.

Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66(6):355–474.

134.

Brecht S, Courtecuisse C, Debieuvre C, et al. Efficacy and safety of duloxetine 60 mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: a randomized controlled trial. J Clin Psychiatry. 2007;68(11):1707–1716.

135.

Pertovaara A. Noradrenergic pain modulation. Prog Neurobiol. 2006;80(2):53–83.

136.

Jones SL, Gebhart GF. Quantitative characterization of ceruleospinal inhibition of nociceptive transmission in the rat. J Neurophysiol. 1986;56(5):1397–1410.

137.

Hayashida K, Eisenach JC. Spinal alpha 2-adrenoceptor-mediated analgesia in neuropathic pain reflects brain-derived nerve growth factor and changes in spinal cholinergic neuronal function. Anesthesiology. 2010;113(2):406–412.

138.

Yang XC, Reis DJ. Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther. 1999;288(2):544–549.

139.

Donertas B, Cengelli Unel C, Aydin S, et al. Agmatine co-treatment attenuates allodynia and structural abnormalities in cisplatin-induced neuropathy in rats. Fundam Clin Pharmacol. Epub 2018 Jan 29.

140.

Smith JC, Whitton PS. Nitric oxide modulates N-methyl-D-aspartate-evoked serotonin release in the raphe nuclei and frontal cortex of the freely moving rat. Neurosci Lett. 2000;291(1):5–8.

141.

Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29(43):13435–13444.

142.

Kim JH, Kim JY, Mun CH, Suh M, Lee JE. Agmatine modulates the phenotype of macrophage acute phase after spinal cord injury in rats. Exp Neurobiol. 2017;26(5):278–286.

143.

Ma SF, Chen YJ, Zhang JX, et al. Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury. Brain Behav Immun. 2015;45:157–170.

144.

Palacios G, Muro A, Verdu E, Pumarola M, Vela JM. Immunohistochemical localization of the sigma1 receptor in Schwann cells of rat sciatic nerve. Brain Res. 2004;1007(1–2):65–70.

145.

de la Puente B, Nadal X, Portillo-Salido E, et al. Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain. 2009;145(3):294–303.

146.

Martuscello RT, Spengler RN, Bonoiu AC, et al. Increasing TNF levels solely in the rat hippocampus produces persistent pain-like symptoms. Pain. 2012;153(9):1871–1882.

147.

Kotagale NR, Shirbhate SH, Shukla P, Ugale RR. Agmatine attenuates neuropathic pain in sciatic nerve ligated rats: modulation by hippocampal sigma receptors. Eur J Pharmacol. 2013;714(1–3):424–431.

148.

Santos AR, Gadotti VM, Oliveira GL, et al. Mechanisms involved in the antinociception caused by agmatine in mice. Neuropharmacology. 2005;48(7):1021–1034.

149.

Regunathan S. Agmatine: biological role and therapeutic potentials in morphine analgesia and dependence. AAPS J. 2006;8(3):E479–E484.

Creative Commons License © 2018 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.