Pharmacological Research Allodynia Lowering

Pharmacological Research 119 (2017) 272–277

Contents lists available at ScienceDirect

Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

Allodynia Lowering Induced by Cannabinoids and Endocannabinoids (ALICE) Livio Luongo a,d,e,∗ , Katarzyna Starowicz b,d , Sabatino Maione a,d , Vincenzo Di Marzo c,d a

Department of Experimental Medicine, Division of Pharmacology, Università della Campania “L. Vanvitelli”, Via Costantinopoli 16, Naples, Italy Pain Pathophysiology Lab, Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland c Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy d Endocannabinoid Research Group, Pozzuoli, Italy e Young Against Pain (YAP) Italian Group, Italy b

a r t i c l e

i n f o

Article history: Received 2 February 2017 Received in revised form 20 February 2017 Accepted 20 February 2017 Available online 22 February 2017 Keywords: Neuropathic pain Cannabinoid system Endocannabinoids Astrocytes Microglia

a b s t r a c t Neuropathic pain is a neurological disorder that strongly affects the quality of life of patients. The molecular and cellular mechanisms at the basis of the neuropathic pain establishment still need to be clarified. Among the neuromodulators that play a role in the pathological pain pathways, endocannabinoids could be deeply involved in both neuronal and non-neuronal mechanisms responsible for the appearance of tactile allodynia. Indeed, the function and dysfunction of this complex system in the molecular and cellular mechanisms of chronic pain induction and maintenance have been widely studied over the last two decades. In this review article, we highlighted the possible modulation of the endocannabinoid system in the neuronal, glial and microglial modulation in neuropathic pain treatment. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Chronic pain management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Endocannabinoidome and neuropathic pain establishment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Cannabinoid and neuroinflammatory processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Cannabinoid use in human pain-associated diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

1. Chronic pain management Neuropathic pain is a devastating condition which has a serious impact on the quality of life of patients. It represents a very tricky-to-treat consequence of damages to the peripheral or central nervous systems (PNS or CNS) that are associated with a rearrangement of spinal and supraspinal areas resulting in the exacerbation of pain message [1]. After CNS or PNS injuries, thermal and mechanical painful stimuli are integrated as amplified (hyperalgesia), while

∗ Corresponding author at: Department of Experimental Medicine, Division of Pharmacology, Università della Campania “L. Vanvitelli”, Via Costantinopoli 16, Naples, Italy. E-mail address: [email protected] (L. Luongo). http://dx.doi.org/10.1016/j.phrs.2017.02.019 1043-6618/© 2017 Elsevier Ltd. All rights reserved.

innocuous one are elaborated as aching (allodynia). Thus, neuropathic pain represents a real neurological dysfunction that is characterized by as yet scarcely investigated neurophysiological and neurobiochemical pathways. Nowadays, weak pharmacological approaches exist to manage abnormal pain, which is very often not responsive even to opioids and other pain killers commonly used in several pain conditions. Therapeutic compounds available include: 1) gabapentinoids such as gabapentin and pregabalin, representing the therapy of choice for the post-herpetic neuralgia

L. Luongo et al. / Pharmacological Research 119 (2017) 272–277

2) opioid derivatives, in particular, those with the hybrid mechanism of action and lower affinity for the opioid receptor, such as tramadol and tapentadol 3) several types of antidepressants such as amitriptyline – which still represents one of the most useful drugs in the clinic but is associated with several adverse reactions – duloxetine and others 4) non-steroidal anti-inflammatory drugs (NSAIDs), some of which used for chronic pain conditions 5) carbamazepine as the first choice for trigeminal neuralgia 6) local anaesthetics such as lidocaine patches. 7) TRPV1 modulators such as capsaicin patches 8) adjuvant drugs such as vitamin B12 complex, acetyl-carnitine, bisphosphonates and corticosteroids. Despite this huge therapeutic arsenal, several forms of neuropathic pain are still scarcely treated and need an improvement of the target-specific molecules. 2. Endocannabinoidome and neuropathic pain establishment Among the pharmacological approaches that have been proposed for neuropathic pain treatment, the pharmacological manipulation of cannabinoid receptors, by natural or synthetic agonists, or indirectly by selective blockers of enzymes involved in the endocannabinoid degradation fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), is largely sustained by recent preclinical studies in experimental animal models [2–4]. Evidence highlights that cannabinoid receptor-targeted ligands might be effective in several animal models of neuropathic pain [5,2,6–9]. Reports of cannabinoid-based therapies are also available [10,11]. However, even though there is evidence of endocannabinoid level changes in tissues from neuropathic pain-affected animals [12], the role of these lipids in tactile allodynia induction and maintenance is still highly debated. Indeed, recent evidence showed that the CB1 deletion is associated with enhancement of cold allodynia, whereas a recovery of tactile allodynia was also observed after two weeks in the spared nerve injury (SNI) model of neuropathic pain [13], whereas in other models of neuropathic pain this discrepant effect is not evident. The phenotype of the global deletion of CB1 receptor (CB1R) might be surely associated with compensatory mechanisms that could explain, at least in part, the paradoxical effect revealed in SNI-induced allodynia (e.g. increased levels in microglia of CB2 receptors [CB2R]), whose stimulation has been reported to be antiallodynic [14,15]. Until now, the main symptoms associated with neuropathic pain have been thought to derive mainly from the neuronal maladaptive processes. Recent reports, however, have clearly demonstrated that central and peripheral immune system cells represent the key regulators of the establishment of symptoms like hyperalgesia and allodynia following an injury to the nervous system. Indeed, it has been shown that astrocytes and microglia drive the neuroinflammatory processes within the spinal cord and actively contribute to the development and progression of the tactile allodynia [16]. Interestingly, microglia have been shown to express cannabinoid receptors [17] and to produce and inactivate endocannabinoids [18,19]. Originally, the endocannabinoid system was believed to be composed of the two G-protein-coupled cannabinoid (CB) receptors, CB1R and CB2R; their endogenously produced ligands, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2AG) and the metabolic machinery for these lipids including enzymes such as FAAH and MAGL [20]. The latest version of the system is more complex and includes several other

273

endocannabinoid-like mediators involved in pain processes, putative receptors and enzymes as well as endocannabinoid metabolites with their own receptors. Furthermore, AEA and 2-AG have been shown to exert several effects via other targets as well, such as the transient receptor potential vanilloid-type 1 (TRPV1) channel, other TRP channels (i.e. TRPM8 or TRPA1), GPR18, GPR55, T-type calcium channels, glycine receptors and GABAA receptor [21–24]. Other mediators, such as two other ethanolamides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), the lipoaminoacid N-arachidonoyl-glycine [25,26], as well as cycloxygenase-derived metabolites “ prostamides” [27], have been shown to be involved in the abnormal pain perception associated with the peripheral injuries by modulating many receptors, including TRPV1 channels, peroxisome proliferator-activated nuclear receptor-! (PPAR-!), and yet-to-be-fully characterized proteins [28]. Therefore, the term “endocannabinoidome” has been recently proposed for this complex lipid system [26]. The two recognised receptors CB1 and CB2 share very similar, although not identical, signal transduction pathways but have different localization in mammals. In particular, CB1R is abundantly expressed in the CNS areas involved in pain modulation such as the periaqueductal grey (PAG), rostral ventromedial medulla (RVM), hippocampus and cortex and in the spinal cord [29,30]. However, evidence shows that CB1R is also located in the peripheral sites and could play an important role in some pathological states [31,32]. The CB2R is mainly expressed in immune cells of either the periphery, such as macrophages, dendritic cells and T-cells, or the CNS, such as microglia. Indeed, CB2R over-expression in the dorsal horn of spinal cord of neuropathic animals has been shown in microglial cells and astrocytes and its modulation results in a neuroprotective effect [33,34]. Moreover, it has been reported that CB2R play a key role in driving the neuro-immune response in the spinal dorsal horn during neuropathic pain [14,15]. Other receptors have been suggested to mediate endocannabinoid actions. In particular, TRPV1 and other TRP channels might be activated by high concentrations of AEA and other endocannabinoid-like compounds such as OEA, as well as several plant-derived phytocannabinoids such as cannabidiol (CBD) [35], and seems to be involved in the enhancement of phagocytosis in microglia cells [36]. Importantly, the modulation of the biochemical machinery for the production and degradation of the endocannabinoids (e.g. FAAH or MAGL inhibitors) has been shown to alter pain transmission. Besides this indirect pharmacological strategy, also the direct activation of CBRs showed efficacy at reducing pain in preclinical animal models. Unfortunately, CB1R-induced analgesia is often linked with unpleasant effects, such as sedation, psychoticlike behaviour, addiction, tolerance and cognitive impairment. These effects limit the clinical use of compounds that activate the CB1R. Also, CB2R activation has been reported to alleviate inflammatory and neuropathic pain and to reduce motor impairments in models of neurodegenerative diseases [37–40,14,15,41,42,8]. Importantly, CB2R-mediated effects seem to be associated with less psychotropic actions since are mainly due to non-neuronal pathways. Peripheral sites of action of CB2R agonists in both inflammatory and neuropathic pain models have been identified [43,44], even though the specific mechanisms are still debated. This evidence is supported by studies suggesting an over-expression of CB2R mRNA and/or protein in the spinal dorsal horn in animal models of neuropathic pain. In particular, the over-expression of both CB2R mRNA and protein has been shown to be localized in the spinal dorsal horn activated microglia [33,14,15] (Fig. 1). Overexpression of CB2R or application of its agonists reduces microglial activation and neuropathic pain symptoms while treatment with CB2R antagonists blocks these effects in various neuropathic pain models. [45–47], Also systemic administration of CB2R agonists

274


Fig. 1. Schematic representation of microglia CB2R action in chronic pain. Resting microglia express functional CB2R (A), which becomes upregulated upon microglia activation (B). Upregulation of CB2R or its activation by CB2R agonists decreases the release of pro-inflammatory mediators from microglia and alleviates chronic pain symptoms i.e. allodynia and hyperalgesia (C).

prevents microglial activation and alleviates neuropathic pain symptoms in STZ rats [48]. The function of CB2R has been also investigated by a recent research by Landry and collaborators, who demonstrated that CB2R-mediated anti-allodynic effects were due to the reduction of mitogen-activated protein kinase phosphorylation in the spinal dorsal horn [42]. The role of CB2R in the induction of abnormal pain through an immune mechanism has been linked to IFN-" activity [14]. The activity of CB2R in microglial cells would reduce the activation of these cells during neuropathic pain by regulating the expression of iNOS and CCR2 [14]. Results of in vitro studies have shown that CB2R activation in microglia stimulates phosphatases that inhibit the ERK pathway, thus decreasing TNF! expression and chemotaxis mediated by ADP in microglia [49]. Recently, several new CB2R modulators have been proposed also based on new medicinal chemistry approaches [50]. Despite the promising therapeutic potential showed by CB2R agonists, their translational success depends also by some limitations, such as immune suppression upon chronic use- or paradoxical pro-inflammatory actions [50]. Moreover, a CB2R-mediated effect was also shown on the modulation of the endocannabinoid biosynthetic machinery [51]. Indeed, another opportunity to limit the CB1R-associated side effects could be to pharmacologically modulate the enzymes responsible of the endocannabinoids degradation [12,52]. In fact, these molecules are synthesized and metabolized ‘on demand’ [53] in several pathophysiological conditions, including inflammatory and abnormal pain [12,54]. Thus, inhibition of enzymes catalysing endocannabinoid degradation would activate CB1R specifically at sites of elevated endocannabinoid turnover, avoiding the interference with other populations of these receptors and, in turn, limiting their side effects [53]. Other strategies have been suggested with hybrid drugs blocking FAAH and antagonizing TRPV1 channels that also exert antinociception in several models of neuropathic pain [55,56]. Moreover, also the dual blockade of FAAH and COX2 have been proposed [57,58]. This strategy would be beneficial since the increase in the endocannabinoids such as anandamide or 2-AG can generate, via COX2-mediated routes, several pro-hyperalgesic products such as prostamide F2! [27]. 3. Cannabinoid and neuroinflammatory processes It is recently recognized that several forms of chronic/neuropathic pain are also associated with neuroinflam-

matory processes involving non-neuronal cells such as astrocytes and microglia [59–66]. In view of these important and complex cellular networks, the endocannabinoid system may represent a potential tool for the modulation of microglia/astrocyte/neuron communications. In fact, endocannabinoids are also produced in astrocytes and microglia [67]. Interestingly, it was suggested that microglia produce higher amounts of endocannabinoids with respect to neurons and astrocytes. Enhanced levels of 2-AG after painful stimuli were reported at the spinal and supraspinal level in several models of neuropathic pain [12,55]. 2-AG is involved in the microglia motility (morphological rearrangement), proliferation and migration, and it has been proposed that 2-AG biosynthesized by microglia increases their proliferation in a CB2R-dependent manner [18]. In addition, 2-AG also induces the migration of microglia in the direction of dying cells. Also, this process is mediated partly by CB2R and by an as yet uncharacterized microglial “abn-CBD receptor” [17]. Intriguingly, it has been proposed that 2-AG microglial degradation is due to the action of an enzyme called a,b-hydrolase 6. Selective blockers of this enzyme were recently proposed [68,69]. These compounds increase the 2-AG levels and, in turn, shift macrophage/microglia phenotypes from the activated (M1) to the so-called alternatively activated (M2) one [70] (Fig. 1). Moreover, a recent report showed that CB2R agonists decrease cytokine release from microglial cells in vitro [71], and this could represent one of the mechanisms through which these molecules reduce neuropathic symptoms. A puzzling network of multicellular cross-talk involving endocannabinoids, their enzymes, cannabinoid, glutamate and TRPV1 receptors, on the one hand, and neurons, astrocytes and microglia, on the other hand, was recently proposed to be at the basis of some of the prefrontal cortex alterations induced by neuropathic pain [55]. The authors reported that spared nerve injury model of neuropathic pain (SNI) is associated with enhanced excitatory signalling in the pre-/infralimbic cortex, as well as by upregulation of TRPV1 receptors in glutamatergic terminals and somata in this region of the brain. These two events concur at inducing glutamate spillover, which might, in turn, stimulate both pro-nociceptive and anti-nociceptive mechanisms [55] (Fig. 2). Interestingly, also PEA was shown to modulate glutamatergic synapses in the prefrontal cortex during neuropathic pain [72]. PEA is an endogenous lipid affine to the family of the fatty acid ethanolamides (FAEs) which derives from the reaction between ethanolamine and palmitic acid and is called “endocannabinoid-like molecule”. PEA is highly expressed in mam-


275

Fig. 2. Cannabinoid-mediated action in the pre-/infralimbic (PL/IL) cortex in neuropathic pain. Pro-nociceptive mechanisms are mostly due to the AMPA receptor stimulation while anti-nociceptive action requests NMDA receptors by glutamate. Glutamate release can also be controlled by biosynthesis and release of 2-AG from TRPV1-expressing perikarya. A retrograde activation of CB1R results in a reduction in glutamate release.

malian brain and exerts important pharmacological effects when supplied exogenously as a drug [73,74], or when its endogenous levels are increased by the inhibition of its metabolism [75]. In particular, PEA has been shown to be involved in the neuroprotective mechanisms activated under several pathological states, including chronic and neuropathic pain [76,72,77,78] and other CNS-related disorders associated with neuroinflammation [79]. 4. Cannabinoid use in human pain-associated diseases The high amount of evidence reporting the efficacy of the cannabinoid system pharmacological manipulation in preclinical models of chronic and neuropathic pain, allowed the clinicians to start several clinical trials using cannabinoids in several chronic pain-associated diseases. In particular, it has been reported their efficacy in complex multi-pain syndrome such as fibromyalgia [11]. It has been reported the possibility to use nabilone for the management of pain [80]. Interestingly, nabiximols has been approved as a botanical drug in the United Kingdom in 2010 as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder and other symptoms associated with multiple sclerosis [81,82]. 5. Conclusions The pharmacological manipulation of the endocannabinoid system could represent a new target in the management of those types of neuropathic pain that remain untreatable with the commercially available pain killers. The advantage of endocannabinoid-based therapies would consist of the targeting not only neurons but also astroglia and microglia that are the early players in the establishment of tactile allodynia. Intriguingly, the cannabinoid-based therapy is also available for human diseases associated with abnormal pain such as fibromyalgia and multiple sclerosis. Funding The study is supported by National Science Centre (NCN) grant OPUS UMO-2014/13/B/NZ7/02311.

References [1] J.J. Bonica, Pain-basic principles of management, Northwest Med. 69 (8) (1970) 567–568. [2] P. Goya, N. Jagerovic, L. Hernandez-Folgado, M.I. Martin, Cannabinoids and neuropathic pain, Mini Rev. Med. Chem. 3 (7) (2003) 765–772. [3] N. Malek, M. Kostrzewa, W. Makuch, A. Pajak, M. Kucharczyk, F. Piscitelli, B. Przewlocka, V. Di Marzo, K. Starowicz, The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain, Pharmacol. Res. 111 (2016) 251–263. [4] S. Maione, T. Bisogno, V. de Novellis, et al., Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors, J. Pharmacol. Exp. Ther. 316 (3) (2006) 969–982. [5] R.G. Pertwee, Cannabinoid receptors and pain, Prog. Neurobiol. 63 (2001) 569–611, Review. [6] B. Costa, A.E. Trovato, M. Colleoni, G. Giagnoni, E. Zarini, T. Croci, 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 116 (2005) 52–61. [7] M.D. Jhaveri, D.R. Sagar, S.J. Elmes, D.A. Kendall, V. Chapman, Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain, Mol. Neurobiol. 36 (2007) 26–35, Review. [8] H. Ikeda, M. Ikegami, M. Kai, M. Ohsawa, J. Kamei, Activation of spinal cannabinoid CB2 receptors inhibits neuropathic pain in streptozotocininduced diabetic mice, Neuroscience 250 (2013) 446–454. [9] F. Vincenzi, M. Targa, C. Corciulo, M.A. Tabrizi, S. Merighi, S. Gessi, G. Saponaro, P.G. Baraldi, P.A. Borea, K. Varani, Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models, Pain 154 (2013) 864–873. [10] L.A. Smith, F. Azariah, V.T. Lavender, N.S. Stoner, S. Bettiol, Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy, Cochrane Database Syst. Rev. 11 (2015) CD009464, http://dx.doi.org/10.1002/ 14651858, Review. [11] B. Walitt, P. Klose, M.A. Fitzcharles, T. Phillips, W. Häuser, Cannabinoids for fibromyalgia, Cochrane Database Syst. Rev. 7 (2016) CD011694. [12] S. Petrosino, E. Palazzo, V. de Novellis, T. Bisogno, F. Rossi, S. Maione, V. Di Marzo, Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats, Neuropharmacology 52 (2007) 415–422. [13] A. Sideris, B. Piskoun, L. Russo, M. Norcini, T. Blanck, E. Recio-Pinto, Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity, Mol. Pain (2016) 12. ˜ [14] I. Racz, X. Nadal, J. Alferink, J.E. Banos, J. Rehnelt, M. Martín, B. Pintado, A. Gutierrez-Adan, E. Sanguino, J. Manzanares, A. Zimmer, R. Maldonado, Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain, J. Neurosci. 28 (2008) 12125–12135.

276


[15] L. Luongo, E. Palazzo, S. Tambaro, C. Giordano, L. Gatta, M.A. Scafuro, F.S. Rossi, P. Lazzari, L. Pani, V. de Novellis, M. Malcangio, S. Maione, 1-(2′ ,4′ -dichlorophenyl)-6-methyl-N-cyclohexylamine1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice, Neurobiol. Dis. 37 (2010) 177–185. [16] L.R. Watkins, E.D. Milligan, Maier SF.Spinal cord glia: new players in pain, Pain 93 (3) (2001) 201–205. [17] L. Walter, A. Franklin, A. Witting, C. Wade, Y. Xie, G. Kunos, K. Mackie, N. Stella, Nonpsychotropic cannabinoid receptors regulate microglial cell migration, J. Neurosci. 23 (4) (2003) 1398–1405. [18] E.J. Carrier, C.S. Kearn, A.J. Barkmeier, et al., Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism, Mol. Pharmacol. 65 (4) (2004) 999–1007. [19] N. Stella, Endocannabinoid signaling in microglial cells, Neuropharmacology 56 (Suppl. 1) (2009) 244–253. [20] P. Anand, G. Whiteside, C.J. Fowler, A.G. Hohmann, Targeting CB2 receptors and the endocannabinoid system for the treatment of pain, Brain Res. Rev. 60 (2009) 255–266, Review. [21] N.S. Singh, M. Bernier, I.W. Wainer, Selective GPR55 antagonism reduces chemoresistance in cancer cells, Pharmacol. Res. 111 (2016) 757–766. [22] G.E. Yevenes, H.U. Zeilhofer, Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids, PLoS One 6 (2011) e23886. [23] L. De Petrocellis, K. Starowicz, A.S. Moriello, M. Vivese, P. Orlando, V. Di Marzo, Regulation of transient receptor potential channels of melastatin type 8 (TRPM8): effect of cAMP, cannabinoid CB(1) receptors and endovanilloids, Exp. Cell Res. 313 (2007) 1911–1920. [24] E. Sigel, R. Baur, I. Racz, J. Marazzi, T.G. Smart, A. Zimmer, J. Gertsch, The major central endocannabinoid directly acts at GABA(A) receptors, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 18150–18155. [25] M. Oz, Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids, Pharmacol. Ther. 111 (2006) 114–144, Review. [26] S. Maione, B. Costa, V. Di Marzo, Endocannabinoids: a unique opportunity to develop multitarget analgesics, Pain 154 (2013) S87–S93. [27] L. Gatta, F. Piscitelli, C. Giordano, S. Boccella, A. Lichtman, S. Maione, V. Di Marzo, Discovery of prostamide F2a and its role in inflammatory pain and dorsal horn nociceptive neuron hyperexcitability, PLoS One 7 (2012) e31111. [28] L. Luongo, S. Maione, V. Di Marzo, Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions, Eur. J. Neurosci. 39 (3) (2014) 401–408, Review. [29] L. Cristino, L. de Petrocellis, G. Pryce, D. Baker, V. Guglielmotti, V. Di Marzo, Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain, Neuroscience 139 (4) (2006) 1405–1415. [30] B. Paniagua-Torija, A. Arevalo-Martin, I. Ferrer, E. Molina-Holgado, D. Garcia-Ovejero, CB1 cannabinoid receptor enrichment in the ependymal region of the adult human spinal cord, Sci. Rep. 5 (2015) 17745. [31] J. Sousa-Valente, A. Varga, J.V. Torres Perez, A. Jenes, J. Wahba, K. Mackie, B. Cravatt, N. Ueda, K. Tsuboi, P. Santha, G. Jancso, H. Tailor, A. Avelino, I. Nagy, Inflammation of peripheral tissues and injury to peripheral nerves induce diferring effects in the expression of the calcium-sensitive anandamide-synthesising enzyme and related molecules in rat primary sensory neurons, J. Comp. Neurol. (2016), http://dx.doi.org/10.1002/cne. 24154, in press. [32] J. Desroches, S. Charron, J.F. Bouchard, P. Beaulieu, Endocannabinoids decrease neuropathic pain-related behavior in mice through the activation of one or both peripheral CB1 and CB2 receptors, Neuropharmacology 77 (2014) 441–452. [33] J. Zhang, C. Hoffert, H.K. Vu, T. Groblewski, S. Ahmad, D. O’Donnell, Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models, Eur. J. Neurosci. 17 (2003) 2750–2754. ˜ ˜ [34] M. Gómez-Canas, P. Morales, L. García-Toscano, C. Navarrete, E. Munoz, N. Jagerovic, J. Fernández-Ruiz, M. García-Arencibia, M.R. Pazos, Biological characterization of PM226, a chromenoisoxazole, as a selective CB2 receptor agonist with neuroprotective profile, Pharmacol. Res. 110 (2016) 205–215. [35] F.A. Iannotti, C.L. Hill, A. Leo, A. Alhusaini, C. Soubrane, E. Mazzarella, E. Russo, B.J. Whalley, V. Di Marzo, G.J. Stephens, Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability, ACS Chem. Neurosci. 5 (11) (2014) 1131–1141. [36] S. Hassan, K. Eldeeb, P.J. Millns, A.J. Bennett, S.P. Alexander, D.A. Kendall, Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation, Br. J. Pharmacol. 171 (9) (2014) 2426–2439. [37] A. Calignano, G. La Rana, A. Giuffrida, D. Piomelli, Control of pain initiation by endogenous cannabinoids, Nature 394 (1998) 277–281. [38] N. Clayton, F.H. Marshall, C. Bountra, C.T. O’shaughnessy, CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain, Pain 96 (2002) 253–260. [39] K.J. Valenzano, L. Tafesse, G. Lee, J.E. Harrison, J.M. Boulet, S.L. Gottshall, L. Mark, M.S. Pearson, W. Miller, S. Shan, L. Rabadi, Y. Rotshteyn, S.M. Chaffer, P.I. Turchin, D.A. Elsemore, M. Toth, L. Koetzner, G.T. Whiteside, Pharmacological and pharmacokinetic characterization of the cannabinoid

[40]

[41]

[42]

[43]

[44]

[45]

[46] [47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy, Neuropharmacology 48 (2005) 658–672. M. Beltramo, N. Bernardini, R. Bertorelli, M. Campanella, E. Nicolussi, S. Fredduzzi, A. Reggiani, CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms, Eur. J. Neurosci. 23 (2006) 1530–1538. C. Palomo-Garo, Y. Gómez-Gálvez, C. García, J. Fernández-Ruiz, Targeting the cannabinoid CB2 receptor to attenuate the progression of motor deficits in LRRK2-transgenic mice, Pharmacol. Res. 110 (2016) 181–192. R.P. Landry, E. Martinez, J.A. DeLeo, E.A. Romero-Sandoval, Spinal cannabinoid receptor type 2 agonist reduces mechanical allodynia and induces mitogen-activated protein kinase phosphatases in a rat model of neuropathic pain, J. Pain 13 (2012) 836–848. M.M. Ibrahim, H. Deng, A. Zvonok, D.A. Cockayne, J. Kwan, H.P. Mata, T.W. Vanderah, J. Lai, F. Porreca, A. Makriyannis, T.P. Malan Jr, Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 10529–10533. G.T. Whiteside, S.L. Gottshall, J.M. Boulet, S.M. Chaffer, J.E. Harrison, M.S. Pearson, P.I. Turchin, L. Mark, A.E. Garrison, K.J. Valenzano, A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833, Eur. J. Pharmacol. 528 (2005) 65–72. P.J. Austin, G. Moalem-Taylor, The neuro-immune balance in neuropathic pain:involvement of inflammatory immune cells, immune-like glial cells and cytokines, J. Neuroimmunol. 229 (1–2) (2010) 26–50, 3, 11. K. Inoue, M. Tsuda, Microglia and neuropathic pain, Glia 57 (14) (2009) 1469–1479. C.C. Toth, N.M. Jedrzejewski, C.L. Ellis, W.H. Frey II, Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain, Mol. Pain 6 (2010) 16. N.M. Jedrzejewski, C.L. Ellis, W.H. Frey II, Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain, Mol. Pain 6 (2010) 16. E.A. Romero-Sandoval, R. Horvath, R.P. Landry, J.A. DeLeo, Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation, Mol. Pain 5 (2009) 25. G. Navarro, P. Morales, C. Rodríguez-Cueto, J. Fernández-Ruiz, N. Jagerovic, R. Franco, Targeting cannabinoid CB2 receptors in the central nervous system: medicinal chemistry approaches with focus on neurodegenerative disorders, Front. Neurosci. 10 (2016) 406, Review. M. Brindisi, S. Maramai, S. Gemma, S. Brogi, A. Grillo, L. Di Cesare Mannelli, E. Gabellieri, S. Lamponi, S. Saponara, B. Gorelli, D. Tedesco, T. Bonfiglio, C. Landry, K.M. Jung, A. Armirotti, L. Luongo, A. Ligresti, F. Piscitelli, C. Bertucci, M.P. Dehouck, G. Campiani, S. Maione, C. Ghelardini, A. Pittaluga, D. Piomelli, V. Di Marzo, S. Butini, Development and pharmacological characterization of selective blockers of 2-arachidonoyl glycerol degradation with efficacy in rodent models of multiple sclerosis and pain, J. Med. Chem. 59 (6) (2016) 2612–2632. R. Russo, J. Loverme, G. La Rana, T.R. Compton, J. Parrott, A. Duranti, A. Tontini, M. Mor, G. Tarzia, A. Calignano, D. Piomelli, 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. 322 (1) (2007) 236–242. V. Di Marzo, Endocannabinoids and other fatty acid derivates with cannabimimetic properties: biochemistry and possible physiopathological relevance, Biochim. Biophys. Acta 1392 (1998) 153–175. L. Guasti, D. Richardson, M. Jhaveri, K. Eldeeb, D. Barrett, M.R. Elphick, S.P. Alexander, D. Kendall, G.J. Michael, V. Chapman, Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain, Mol. Pain 5 (2009) 35. C. Giordano, L. Cristino, L. Luongo, D. Siniscalco, S. Petrosino, F. Piscitelli, I. Marabese, L. Gatta, F. Rossi, R. Imperatore, E. Palazzo, V. de Novellis, V. Di Marzo, S. Maione, TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception, Cereb. Cortex 22 (2012) 2495–2518. V. de Novellis, D. Vita, L. Gatta, L. Luongo, G. Bellini, M. De Chiaro, I. Marabese, D. Siniscalco, S. Boccella, F. Piscitelli, V. Di Marzo, E. Palazzo, F. Rossi, S. Maione, The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats, Mol. Pain 7 (2011) 7. M. Migliore, D. Habrant, O. Sasso, C. Albani, S.M. Bertozzi, A. Armirotti, D. Piomelli, R. Scarpelli, Potent multitarget FAAH-COX inhibitors: design and structure-activity relationship studies, Eur. J. Med. Chem. 109 (2016) 216–237. O. Sasso, M. Migliore, D. Habrant, A. Armirotti, C. Albani, M. Summa, G. Moreno-Sanz, R. Scarpelli, D. Piomelli, Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage, FASEB J. 29 (6) (2015) 2616–2627. F. Guida, R. Lattanzi, S. Boccella, D. Maftei, R. Romano, V. Marconi, G. Balboni, S. Salvadori, M.A. Scafuro, V. de Novellis, L. Negri, S. Maione, L. Luongo, PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice, Pharmacol. Res. 91 (2015) 36–46.

L. Luongo et al. / Pharmacological Research 119 (2017) 272–277 [60] Y. Liu, L.J. Zhou, J. Wang, D. Li, W.J. Ren, J. Peng, X. Wei, T. Xu, W.J. Xin, R.P. Pang, Y.Y. Li, Z.H. Qin, M. Murugan, M.P. Mattson, L.J. Wu, X.G. Liu, TNF-! differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury, J. Neurosci. 37 (4) (2017) 871–881. [61] M. Kobayashi, H. Konishi, A. Sayo, T. Takai, H. Kiyama, TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain, J. Neurosci. 36 (43) (2016) 11138–11150. [62] S. Koyanagi, N. Kusunose, M. Taniguchi, T. Akamine, Y. Kanado, Y. Ozono, T. Masuda, Y. Kohro, N. Matsunaga, M. Tsuda, M.W. Salter, K. Inoue, S. Ohdo, Glucocorticoid regulation of ATP release from spinal astrocytes underlies diurnal exacerbation of neuropathic mechanical allodynia, Nat. Commun. 7 (2016) 13102. [63] J. Peng, N. Gu, L. Zhou, U.B. Eyo, M. Murugan, W.B. Gan, L.J. Wu, Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury, Nat. Commun. 7 (2016) 12029. [64] S. Beggs, M.W. Salter, SnapShot: microglia in disease, Cell 165 (5) (2016), 1294-1294. [65] F. Denk, M. Crow, A. Didangelos, D.M. Lopes, S.B. McMahon, Persistent alterations in microglial enhancers in a model of chronic pain, Cell Rep. 15 (8) (2016) 1771–1781. [66] Z. Guan, J.A. Kuhn, X. Wang, B. Colquitt, C. Solorzano, S. Vaman, A.K. Guan, Z. Evans-Reinsch, J. Braz, M. Devor, S.L. Abboud-Werner, L.L. Lanier, S. Lomvardas, A.I. Basbaum, Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain, Nat. Neurosci. 19 (1) (2016) 94–101. [67] L. Walter, A. Franklin, A. Witting, T. Moller, N. Stella, Astrocytes in culture produce anandamide and other acylethanolamides, J. Biol. Chem. 277 (2002) 20869–20876. [68] W.R. Marrs, J.L. Blankman, E.A. Horne, A. Thomazeau, Y.H. Lin, J. Coy, A.L. Bodor, G.G. Muccioli, S.S. Hu, G. Woodruff, S. Fung, M. Lafourcade, J.P. Alexander, J.Z. Long, W. Li, C. Xu, T. MD oller, K. Mackie, O.J. Manzoni, B.F. Cravatt, N. Stella, The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors, Nat. Neurosci. 13 (2010) 951–957. [69] K.L. Hsu, K. Tsuboi, A. Adibekian, H. Pugh, K. Masuda, B.F. Cravatt, DAGLb inhibition perturbs a lipid network involved in macrophage inflammatory responses, Nat. Chem. Biol. 8 (2012) 999–1007. [70] F. Tchantchou, Y. Zhang, Selective inhibition of alpha/beta-hydrolase domain 6 attenuates neurodegeneration, alleviates blood brain barrier breakdown, and improves functional recovery in a mouse model of traumatic brain injury, J. Neurotrauma 30 (2013) 565–579. [71] S. Merighi, S. Gessi, K. Varani, D. Fazzi, P. Mirandola, P.A. Borea, Cannabinoid CB(2) receptor attenuates morphine-induced inflammatory responses in activated microglial cells, Brit. J. Pharmacol. 166 (2012) 2371–2385.

277

[72] F. Guida, L. Luongo, F. Marmo, R. Romano, M. Iannotta, F. Napolitano, C. Belardo, I. Marabese, A. D’Aniello, D. De Gregorio, F. Rossi, F. Piscitelli, R. Lattanzi, A. de Bartolomeis, A. Usiello, V. Di Marzo, V. de Novellis, S. Maione, Palmitoylethanolamide reduces pain-related behaviors and restores glutamatergic synapses homeostasis in the medial prefrontal cortex of neuropathic mice, Mol. Brain 8 (2015) 47. [73] J. Lo Verme, J. Fu, G. Astarita, G. La Rana, R. Russo, A. Calignano, D. Piomelli, The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide, Mol. Pharmacol. 67 (1) (2005) 15–19. [74] J. LoVerme, G. La Rana, R. Russo, A. Calignano, D. Piomelli, The search for the palmitoylethanolamide receptor, Life Sci. 77 (14) (2005) 1685–1698, Review. [75] C. Solorzano, C. Zhu, N. Battista, G. Astarita, A. Lodola, S. Rivara, M. Mor, R. Russo, M. Maccarrone, F. Antonietti, A. Duranti, A. Tontini, S. Cuzzocrea, G. Tarzia, D. Piomelli, Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation, Proc. Natl. Acad. Sci. U. S. A. 106 (49) (2009) 20966–20971. [76] L. Luongo, F. Guida, S. Boccella, G. Bellini, L. Gatta, F. Rossi, V. de Novellis, S. Maione, Palmitoylethanolamide reduces formalin-induced neuropathic-like behaviour through spinal glial/microglial phenotypical changes in mice, CNS Neurol. Disord. Drug Targets 12 (1) (2013) 45–54. [77] G. D’Agostino, C. Cristiano, D.J. Lyons, R. Citraro, E. Russo, C. Avagliano, R. Russo, G.M. Raso, R. Meli, G. De Sarro, L.K. Heisler, A. Calignano, Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice, Mol. Metab. 4 (7) (2015) 28–36. [78] L. Di Cesare Mannelli, A. Pacini, F. Corti, S. Boccella, L. Luongo, E. Esposito, S. Cuzzocrea, S. Maione, A. Calignano, C. Ghelardini, Antineuropathic profile of N-palmitoylethanolamine in a rat model of oxaliplatin-induced neurotoxicity, PLoS One 10 (6) (2015) e0128080. [79] S.D. Skaper, L. Facci, P. Giusti, Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator, Mol. Neurobiol. 48 (2) (2013) 40–52. [80] C.C. Tsang, M.G. Giudice, Nabilone for the management of pain, Pharmacotherapy 36 (3) (2016) 273–286, Review. [81] W. Notcutt, R. Langford, P. Davies, S. Ratcliffe, R. Potts, A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of ® spasticity due to multiple sclerosis who are receiving long-term Sativex (nabiximols), Mult. Scler. 18 (2) (2012) 219–228. [82] J.R. Johnson, D. Lossignol, M. Burnell-Nugent, M.T. Fallon, 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 Manag. 46 (2) (2013) 207–218.