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Neuropathic orofacial pain: Cannabinoids as a therapeutic avenue

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Patrick McDonough a , Joseph P. McKenna a , Christine McCreary a , Eric J. Downer b,∗ a b

Cork University Dental School and Hospital, University College Cork, Cork, Ireland Department of Anatomy and Neuroscience, Western Gateway Building, University College Cork, Cork, Ireland

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Article history: Received 16 May 2014 Received in revised form 7 August 2014 Accepted 9 August 2014 Available online xxx

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Keywords: Neuropathic orofacial pain Cannabinoids Trigeminal neuralgia Persistent idiopathic facial pain Burning mouth syndrome

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1. Introduction

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Neuropathic orofacial pain (NOP) exists in several forms including pathologies such as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN) and postherpetic neuralgia (PHN). BMS and PIFP are classically diagnosed by excluding other facial pain syndromes. TN and PHN are most often diagnosed based on a typical history and presenting pain characteristics. The pathophysiology of some of these conditions is still unclear and hence treatment options tend to vary and include a wide variety of treatments including cognitive behaviour therapy, anti-depressants, anti-convulsants and opioids; however such treatments often have limited efficacy with a great amount of inter-patient variability and poorly tolerated side effects. Analgesia is one the principal therapeutic targets of the cannabinoid system and many studies have demonstrated the efficacy of cannabinoid compounds in the treatment of neuropathic pain. This review will investigate the potential use of cannabinoids in the treatment of symptoms associated with NOP. © 2014 Elsevier Ltd. All rights reserved.

According to the International Association for the Study of Pain (IASP), neuropathic pain is “pain caused by a lesion or disease of the somatosensory nervous system”, and unlike nociceptive and inflammatory pain is associated with noxious impulses originating from abnormalities in neural structures (for review see (Klasser and Gremillion, 2012)). Neuropathic orofacial pain (NOP) is a chronic pain condition involving the head, face, and(or) neck and is associated with dysfunction or primary lesion in the nervous system. Although the precise underlying cause of NOP has not been fully elucidated, both human and animal studies suggest that a number of intricate peripheral and central mechanisms are involved, including metabolic disorder, mechanical trauma,

Abbreviations: 2-AG, 2-arachidonoylglycerol; 5-HT, 5-hydroxytryptamine anandamide N-arachidonoylethanolamide; BMS, burning mouth syndrome; CB, cannabinoid receptor; CBT, cognitive behavioural therapy; CNS, central nervous system; GABA, ␥-Aminobutyric acid; HZ, herpes zoster; IL, interleukin; mGluR, metabotrophic glutamate receptor; MS, Multiple Sclerosis; NO, nitric oxide; NOP, neuropathic orofacial pain; PAG, periaqueductal grey; PET, positron emission tomography; PHN, postherpetic neuralgia; PIFP, persistent idiopathic facial pain; PK, protein kinase; PPAR, peroxisome proliferator-activated receptor; RVM, rostral ventromedial medulla; THC, tetrahydrocannabinol; TN, trigeminal neuralgia; TRPV1, vanilloid channel type 1; Vc, trigeminal nucleus caudalis. ∗ Corresponding author. Tel.: +353 21 4205481. E-mail address: [email protected] (E.J. Downer).

bacterial/viral/fungal infection and tumour growth (Klasser and Gremillion, 2012). These conditions represent a clinical challenge as pain can arise from many sources in the orofacial region, and overall NOP disorders represent a major health concern due to the impact on quality of life and extensive usage of health care facilities (McDermott et al., 2006). Furthermore, several medical disciplines may be involved in NOP disorder diagnoses as patients afflicted with such disorders often present with additional unexplained extraoral comorbidities (Mignogna et al., 2011). NOP preferentially affects women in the fifth decade of life (Rodriguez-Lozano et al., 2010) and the exact prevalence is unknown, with studies reporting prevalence rates ranging from 0.03 to 0.5%, depending on the specific disorder (Berger et al., 2004, Mueller et al., 2011). In addition, the etiology of NOP remains largely unclear, and is linked with central nervous system (CNS) pathologies, systemic disease and traumatic neuropathies associated with dental procedures (Rasmussen et al., 2004) such as endodontic treatment, implant placement, tooth extraction and direct needle trauma (Campbell et al., 1990; Lynch and Elgeneidy, 1996). Although a number of major pain classification systems of relevance to NOP exist, including IASP, the International Headache Society classification system, and the Research Diagnostic Criteria for Temporomandibular Disorders (Zakrzewska, 2004), NOP may be broadly divided into three broad categories: episodic, continuous and combination. Episodic NOP (often referred to as paroxysmal neuralgia) includes pathologies such as trigeminal neuralgia (TN) which is characterized by unilateral short episodes

http://dx.doi.org/10.1016/j.biocel.2014.08.007 1357-2725/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: McDonough P, et al. Neuropathic orofacial pain: Cannabinoids as a therapeutic avenue. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.007

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of intense sharp paroxysmal pain, which may be triggered by a stimulus and presents most commonly in the two lower branches (maxillary V2, mandibular V3) of the trigeminal nerve. Continuous NOP (often referred to as atypical odontalgia, atypical facial pain, persistent idiopathic facial pain and phantom tooth syndrome) is often described as a persistent burning or tingling sensation, similar to those symptoms associated with burning mouth syndrome (BMS) and persistent idiopathic facial pain (PIFP). BMS may be idiopathic (primary) or secondary to local/systemic factors and herein we will focus on the idiopathic variant. BMS is most commonly associated with bilateral, continuous pain commonly affecting the tongue, lower lip and hard palate predominantly in postmenopausal women. BMS is considered neuropathic in origin, with neurodegenerative (Nasri-Heir et al., 2011) and neuroinflammatory processes thought to contribute to the disease (Pezelj-Ribaric et al., 2013). PIFP is associated with continuous unilateral, dull, burning pain localized above the neck, in front of the ear, and most often in the zygomaticomaxillary complex. Limited evidence links PIFP with isolated neurophysiological dysfunction and psychological mechanisms. Combination NOP has been described as aching, continuous burning pain with episodes of intense lancinating pain, which is commonly seen in postherpetic neuralgia (PHN), a condition associated with herpes zoster (HZ) infection. PHN is diagnosed if the pain associated with HZ persists for 3 months post-healing of the vesicular skin lesions related to the condition, with pain localized to the same dermatomes as the HZ rash (Rasmussen et al., 2004). Patients with NOP disorders often present to their dental practitioners with a variety of symptoms including allodynia (pain resulting from a stimulus that does not normally cause pain), burning and altered sensation due to the impact of these disorders. They present a difficult diagnostic challenge as NOPs can often mimic common pathologies of the oral cavity and the adjacent structures such as temporomandibular disorders and myofascial pain syndrome (Dworkin and LeResche, 1992). Inevitably, many patients undergo costly radiological investigations, unnecessary dental procedures and the prescription of medications with poorly tolerated side effects. The pathophysiology of these conditions is unclear and therefore treatment options are variable and include cognitive behavioural therapy (CBT) or pharmaceuticals such as anti-depressants, anti-convulsants and opioids. However, such therapy is not always successful and a body of literature has suggested possible novel cellular/molecular therapies for NOP disorders, including local injection of autologous mesenchymal stem cells (Vickers et al., 2014), regulation of satellite glial cells (Jasmin et al., 2010) and delivery of substance P (Mustafa et al., 2013), endomorphin (Makuch et al., 2013) and cannabinoids (Liang et al., 2007). Here we will focus on cannabinoids, reviewing the potential of the cannabinoid system as an alternative therapy in such debilitating conditions.

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2. Pathogenesis

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2.1. NOP: mechanisms for initiation

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Pain in the orofacial region is most often odontogenic in origin and is commonly associated with infection or traumatic injury (Klasser and Gremillion, 2012). Other sources of pain including neuropathic pain can be diagnostically challenging and may be treated incorrectly as dental pain. Typically neuropathic pain persists following treatment. The underlying mechanisms for such NOP remain unclear, with NOP often presenting idiopathically without any recognizable lesion to the facial structures. Indeed, evidence indicates that tissue damage may not be directly linked to pain-modulating pathways in the CNS (Okeson and de Kanter, 1996). However, nerve injury is strongly linked with pain or

neuropathic manifestations. Unfortunately the cellular mechanisms underlying NOP are poorly understood and several pathophysiological mechanisms have been suggested (Table 1). 2.1.1. BMS pathophysiology BMS is a complex disease which may be of neuropathic etiology, with reduced pain and sensory thresholds. Using human studies alterations in salivary flow, salivary steroid (dehydroepiandrosterone) (Dias Fernandes et al., 2009) and vasodilator (calcitonin gene-related peptide) (Zidverc-Trajkovic et al., 2009) levels have been demonstrated in BMS patients. Interestingly, positron emission tomography (PET) studies have demonstrated altered dopamine D1 and D2 receptor expression in the putamen of BMS patients (Hagelberg et al., 2003b) while Borsani et al. (2014) have recently demonstrated altered expression profiles of the transient receptor potential vanilloid channel type 1 (TRPV1) and cannabinoid receptor (CB) type 1 and type 2 in human tongue epithelial cells. Nasri-Heir et al. (2011) suggest a neurodegenerative component to BMS, with chorda tympani nerve hypofunction associated with the disorder. Interestingly, polymorphism in proinflammatory interleukin (IL)-1␤ has been shown in BMS patients, suggesting that IL-1␤ regulation may be a therapeutic target in BMS patient cytokine pain management (Guimaraes et al., 2006). Indeed recent evidence in support of this indicates that pro-inflammatory cytokines such as IL-6 are increased in the saliva of patients with BMS, suggesting neuroinflammatory processes underlie the disease (Pezelj-Ribaric et al., 2013). 2.1.2. PIFP pathophysiology The pathophysiology of PIFP is poorly understood, with patients often presenting with oral and(or) other psychogenic-related complaints. Indeed, some patients may respond to CBT and(or) tricyclic anti-depressants. PET studies in patients have more recently shown that alterations in blood flow occurs in the anterior cingulum and prefrontal cortex (Derbyshire et al., 1994) and alteration in the expression of D2 receptors in the putamen (Hagelberg et al., 2003a). Overall, various neuropathic mechanisms appear to be operating in PIFP, involving peripheral nerve pathology (Forssell et al., 2007), somatosensory dysfunction and changes in the excitability of primary nociceptive afferents (Koltzenburg et al., 1994). 2.1.3. TN pathophysiology TN may be classified as idiopathic (no clinically obvious neurological cause) or secondary (underlying pathology present). Secondary TN is commonly caused by compression of the trigeminal root by a blood vessel, or by demyelination of the nerve in conditions such as Multiple Sclerosis (MS). The exact mechanism for pain production in TN remains uncertain. Using a rodent model of NOP Sugiyama et al. (2013) demonstrated the role of neuronal nitric oxide (NO) signalling in regulating neural excitability of the trigeminal ganglion following inferior alveolar nerve lesion. Elsewhere, several studies indicate specific receptor involvement in animal models of TN. Indeed, metabotrophic glutamate receptor (mGluR) 5 pathways in the trigeminal nucleus caudalis (Vc) and cervical spine mediate inflammatory tongue pain (Liu et al., 2012). In support of receptor-mediated signalling, nerve injury-induced TN is mediated by receptor tyrosine kinase ErbB3/ErbB2 heterodimers in rats (Ma et al., 2012), while distinct alterations in ␮-opioid receptor expression in the nucleus accumbens has been determined in TN patients using PET, suggesting that alterations in the endogenous ␮-opioid system may be linked with TN (DosSantos et al., 2012). Similarly, using a rat model of V2 injury, Okubo et al. (2013) demonstrate a clear role of serotonergic 5-hydroxytryptamine (5-HT) receptors in the Vc in hyperalgesia, while roles for voltage-gated sodium channels (Eriksson et al., 2005) in trigeminal NOP models has been suggested. Using an in vitro approach, Kuroda et al.

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Table 1 Literature assessing the mechanisms underlying NOP pathophysiolgy. Disorder

Animal/human study

Measurement

Observation

Reference

BMS BMS BMS BMS BMS BMS BMS BMS BMS BMS PIFP

Human Human Human Human Human Human Human Human Human Human Human Human Human

PIFP

Human

Excitability of primary nociceptive afferents

TN

Animal

TN TN TN TN

Animal Animal Human Animal Animal

TN

Animal

Reduced with mGluR5 antagonist Reversal by ErbB3/ErbB2 inhibitor Reduction 5-HT depletion attenuates Vc poststimulus neuronal activity Enhanced Nav1.3/Nav␤3 and reduced Nav1.8/Nav1.9 Mediated by P2X1 , P2X3 , and P2X4 receptors

Liu et al. (2012) Ma et al. (2012) DosSantos et al. (2012) Okubo et al. (2013)

TN

TN

Animal Human Human

PHN

Animal

C-fibre neuron injury

Increased astrocyte GFAP and D-serine synthesis Reduction in epidermis and dermis Increased in left striatum/S1/insula/amygdala and right thalamus. Decreased in frontal cortex Increased

Dieb and Hafidi (2013)

PHN PHN

Orofacial pain following inferior alveolar nerve transection CFA-induced inflammatory tongue pain Whisker pad mechanical allodynia Basal ganglia ␮-opioid receptors Secondary mechanical hyperalgesia after trigeminal infraorbital nerve injury Trigeminal Nav1.3, Nav1.8, Nav1.9, Nav␤3 expression after infraorbital nerve injury ATP-induced increase in [Ca2+ ] in trigeminal neurons Mechanical allodynia after constriction of infraorbital nerve Sensory neurites in skin biopsies Cerebral blood flow

Reduction Reduction Reduction Reduced D1/D2 ratio Increased expression Reduction Increased expression Gene polymorphism Increased expression Hypofunction Increased in anterior cingulum/decreased in prefrontal cortex Reduced D1/D2 ratio Abnormal blink reflex, thermal hyesthesia, warm allodynia Relief of ongoing/stimulus-induced pain by local anaesthetic blocks of nerves supplying symptomatic skin Reduced via NOS inhibition

Dias Fernandes et al. (2009) Dias Fernandes et al. (2009) Zidverc-Trajkovic et al. (2009) Hagelberg et al. (2003b Borsani et al. (2014) Borsani et al. (2014) Borsani et al. (2014) Guimaraes et al. (2006) Pezelj-Ribaric et al. (2013) Nasri-Heir et al. (2011) Derbyshire et al. (1994)

PIFP PIFP

Salivary flow Salivary dehydroepiandrosterone Salivary calcitonin gene-related peptide Putamen D1 and D2 receptors Tongue epithelia TRPV1 Tongue epithelia CB1 Tongue epithelia CB2 – Salivary IL-6 Chorda tympani function Blood flow in anterior cingulum and prefrontal cortex Putamen D2 receptors Peripheral nerve pathology

Hagelberg et al. (2003a) Forssell et al. (2007) Koltzenburg et al. (1994)

Sugiyama et al. (2013)

Eriksson et al. (2005) Kuroda et al. (2012

Oaklander et al. (1998) Liu et al. (2013) Sasaki et al. (2013)

CFA, complete freuds adjuvant; NOS, nitric oxide synthase.

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(2012) demonstrate that cultured rat trigeminal ganglion neurons express functional purinergic P2X1 , P2X3 , and P2X4 receptors, and provide evidence that these receptors mediate nociceptive and NOP pathways. The role of glia in NOP is also well investigated, with clear evidence demonstrating a role of astrocytes in modulating post-traumatic NOP (Dieb and Hafidi, 2013).

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2.1.4. PHN pathophysiology PHN occurs during the proliferation/spread of the HZ virus during an acute HZ infection, which is associated with nerve damage including myelin destruction, deafferentation and sensitization (peripheral and/or central) (Baron, 2008). Indeed, a recent study using a mouse model of PHN indicates that PHN is associated with injury predominantly to sensory C-fibre neurons (Sasaki et al., 2013). Evidence also indicates enhanced levels of leukocytes in areas of CNS degeneration in PHN patients (Bennett and Watson, 2009). Furthermore, skin biopsies of PHN patients reveals a loss of sensory fibres (Oaklander et al., 1998), supporting data that neural damage is a key pathophysiological mechanism underlying PHN. Finally, a recent study by Liu et al. (2013) assessing regional cerebral blood flow using perfusion fMRI, identified a characteristic network of brain connectivity in PHN patients involving the thalamus and striatum, which may be central in processing PHN pain.

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3. Therapy

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3.1. Current NOP therapy

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Due to the complex neuropathophysiology underlying NOP, a thorough history, clinical exam, laboratory and radiological

investigations are required to determine that the diagnosis is neuropathic in origin. Current NOP treatments are similar to other neuropathic pain therapeutics (outlined in Table 2), with the use of anti-convulsants alongside anti-depressants, opioids and CBT. The anti-convulsant carbamazepine is a first-line treatment in TN, however some 30–50% of patients with TN are resistant to therapy. Overall, compared to BMS and PIFP, TN has a better response to pharmacological treatment, however other therapeutics should be sought for patients where primary intervention has proven to be ineffective or poorly tolerated. 3.2. Therapeutic potential of the cannabinoid system in NOP 3.2.1. Cannabinoid characteristics Cannabinoids incorporate the active components of Cannabis sativa (the plant-derived cannabinoids), the endogenous cannabinoids produced in humans and animals (anandamide and 2-arachidonoylglycerol (2-AG) are the most extensively studied), and the synthetic cannabinoid ligands generated in the laboratory (Abood and Martin, 1992). Cannabinoids elicit diverse effects, both in the CNS and peripherally, by activating two Gi/o -coupled cannabinoid receptors CB1 and CB2 , the expression of which has been localized on CNS glia (astrocytes and microglia), neurons, and virtually all immune cells (Galiegue et al., 1995; Iversen, 2000; Tsou et al., 1998). CB1 receptors are localized predominantly at neuronal terminals throughout the CNS where they modulate excitatory and inhibitory neurotransmission, whereas CB2 receptors are primarily expressed on immune cells acting as immunomodulators. CB1 /CB2 couple to a long list of signalling targets (Fig. 1), including adenylyl cyclase, mitogen-activated protein kinases and

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Table 2 Current neuropathic pain and NOP medication/treatment options. Neuropathic pain

PHN

TN

BMS

PIFP

TCAs Carbamazepine Gabapentinoids Lidocaine Pregabalin Duloxitine Lamotrigine Opioids

TCAs Gabapentinoids Pregabalin Lidocaine Varcella vaccination against chicken pox Vaccination against HZ Caspaicin Opioids

Carbamazepine Oxcarbazepine Lamotrigine Gabapentinoids Pregabalin Microvascular decompression Radiofrequency lesioning Balloon compression Glycerol rhizolysis Stereotactic radiosurgery

Clonazepam TCAs Lidocaine Catamua Aloe vera Gabapentinoids Topical capsacin Acupuncture Alpha-lipoic acid

TCAs SSRI SNRI Anti-convusants CBT

BMS, burning mouth syndrome; CBT, cognitive behavioural therapy; HZ, herpes zoster; PHN, postherpetic neuralgia; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic anti-depressant; TN, trigeminal neuralgia.

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ion channels, with diverse effects on cellular function (Pertwee et al., 2010). Importantly, studies in CB1 /CB2 knockout mice have demonstrated that cannabinoid ligands can act independently of the CB receptors (Howlett et al., 2002), with evidence indicating roles for GPR55 (an orphan G protein-coupled receptor) (Sharir and Abood, 2010), transient receptor potential vanilloid type-1 (TRPV1) channel (Zygmunt et al., 1999), and the nuclear receptors peroxisome proliferator-activated receptors (PPARs) (O’Sullivan, 2007) in mediating cannabinoid effects, both in the CNS and peripherally.

The midbrain periaqueductal grey (PAG) plays a central function in regulating pain and analgesia and classically the anti-nociceptive properties of cannabinoids (like opioids) is exerted by modulating a descending pathway which projects to the spine via a brainstem circuit comprising the PAG and rostral ventromedial medulla (RVM) (Basbaum and Fields, 1984). Importantly CB1 is abundantly expressed in this brainstem circuit (Tsou et al., 1998), and much data indicates that endocannabinoids inhibit GABAergic inputs to this circuit (Mitchell et al., 2011; Vaughan et al., 2000). Indeed, the PAG is classically a major site of analgesic action for

Fig. 1. Classic cannabinoid signalling systems and potential cellular targets in NOP disorders Cannabinoid receptor signalling relies on receptor homodimers as functional mediators of signal transduction. Ligand binding to the receptor homodimers recruits distinct cellular second messenger cascades with downstream consequences on cellular function. Receptor activation is classically associated with the inhibition of adenylyl cyclase (AC), which regulates cannabinoid-mediated inhibition of protein kinase A (PKA). Reduction of PKA activity is related to a reduction of gene expression through decreasing cAMP response element (CRE) activity. Furthermore, stimulation of CBRs leads to activation of G-protein coupled inwardly-rectifying K+ channels and A-type K+ channels, and inhibition of Ca2+ (P/Q-type, L-type, N-type) channels. CBRs may also induce elevations in intracellular Ca2+ through G-protein-dependent activation of phospholipase C-␤ (PLC-␤). PLC-␤, which cleaves phosphatidylinositol bisphosphate (PIP2 ) to produce inositol trisphosphate (IP3 ) and diacylglycerol (DAG), leading to the activation of protein kinase C (PKC). This kinase has been shown to phosphorylate TRPV1. In addition, the CBRs regulate the phosphorylation and activation of different members of the family of mitogen activated protein kinases (MAPKs), including extracellular signal regulated kinase-1 and -2 (ERK1/2), p38 MAPK and c-Jun N terminal kinase (JNK), with effects on cellular viability and metabolism. In addition, reduction of PKA activity leads to a decrease in consecutive activation of ERK1/2. After uptake mediated either by passive or facilitated diffusion across the membrane, Anandamide (AEA) is primarily hydrolysed to arachidonic acid (AA) by fatty acid amide hydrolase (FAAH). AEA synthesis is also activated by internal Ca2+ , depolarization and certain metabotropic receptors (not shown). TRPV1 channel opening causes Ca2+ influx and neurotransmitter release. TRPV1 and CB1/2 modulate Ca2+ -dependent and MAPK intracellular signalling pathways which are capable of activation of transcription factors which control the expression inflammatory genes. Finally anandamide can activate the TRPV1 receptor.

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cannabinoids (Finn et al., 2003), and furthermore both levels of 2-AG and anandamide are elevated in this brain region in animal models of chronic pain (Hohmann et al., 2005), suggesting that targeting endocannabinoids may be a potential therapeutic strategy in pain management. C. sativa has a long history of consumption therapeutically and at present cannabis-based medicines are in the clinic: Cesamet® (nabilone; a synthetic derivative of the plant cannabinoid tetrahydrocannabinol; THC); Marinol® (dronabinol; synthetic THC); Sativex® (a combination of plant-derived cannabinoids, THC and cannabidiol), for the treatment/management of various conditions (Pertwee, 2009). Cesamet® has been licensed since 1981 for chemotherapy-induced vomiting and nausea. Cesamet® has a good safety profile and has shown analgesic potential in trials of chronic neuropathic pain (Frank et al., 2008) with little evidence indicating its abuse potential (Ware and St Arnaud-Trempe, 2010), although further follow-up assessment of tolerance/dependence is needed in patients. Marinol® initially entered the clinic in 1985 for chemotherapy-induced nausea and vomiting and in 1992 as an effective appetite stimulant for AIDS patients or in individuals undergoing cancer chemotherapy. In human trials, Marinol® has demonstrated analgesic properties (Cooper et al., 2013), however recent evidence indicates that in chronic noncancer pain patients, Marinol® has similar psychoactive effects to cannabis use (Issa et al., 2014). In 2005 Sativex® , a combination of plant-derived cannabinoids THC and cannabidiol, joined Cesamet® and Marinol® in the clinic. Sativex® has been demonstrated to provide relief of cancerrelated pain (Johnson et al., 2013) and neuropathic pain associated with MS (Rog et al., 2007), in addition to long-term symptomatic improvement of spasticity in MS patients (Notcutt et al., 2012). At present Sativex® is prescribed to alleviate MS-associated neuropathic pain and spasticity with no evidence of intoxication-like symptoms (Serpell et al., 2012) or tolerance with long-term use (Johnson et al., 2013; Rog et al., 2007). Given that the cannabinoid system is linked with all aspects of human physiology, adverse effects have been identified in clinical trials and include dry mouth, muscle weakness, fatigue and dizziness (Pertwee, 2007). However, it is noteworthy that with Sativex® , a therapy delivered as an oromucosal spray, it is possible for patients to optimize the benefit-to-risk ratio by downward self-titration of the dose they administer, and hence titrate slowly to a low dose which provides optimal symptom scores with minimal adverse effects (Serpell et al., 2012; Wade et al., 2004). Overall however, despite the growing clinical use of cannabinoids, their mechanism(s) of therapeutic action are not fully appreciated, and consideration of cannabinoid therapy should be clearly weighed in light of their potential effects on all aspects of the nervous and immune systems. 3.2.2. Cannabinoid cellular targets in NOP Many studies using in vitro approaches, animal models and clinical trials have shown the efficacy of naturally- and synthetically-derived cannabinoids in the treatment of neuropathic pain (Fig. 1). Much data indicate that the synthetic cannabinoid drug WIN55,212-2, has analgesic properties in animal models of trigeminal neuropathic pain. Indeed, WIN55,212-2, inhibits allodynia and hyperalgesia following constriction injury of the infraorbital branch of the trigeminal nerve via activation of CB1 (Liang et al., 2007). Elsewhere Liang et al. (2004) demonstrate that WIN55,212-2 attenuates neurotransmission at trigeminal nociceptive synapses via CB1 dependent inhibition of N-type Ca2+ channels. In support of this, WIN55,212-2 modulates ␥-Aminobutyric acid (GABA)- (Li et al., 2009) and 5-HT3 receptor-activated (Shi et al., 2012) currents in trigeminal neurons, providing a mechanism underlying the modulation of analgesia by this cannabinoid. In addition, cannabinoids have the proclivity to target TRPV1, and

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evidence indicates that WIN55,212-2 targets protein kinase A (PKA)/protein kinase C (PKC) signalling systems to inhibit TRPV1 in trigeminal neurons (Wang et al., 2012). In addition to WIN55,212-2, some limited evidence also indicates that the endogenous cannabinoid anandamide targets TRPV1 on trigeminal neurons to modulate neural excitability (Price et al., 2004). 3.2.3. Potential cannabinoid therapeutic mechanisms in BMS, PIFP, TN and PHN Although some studies have investigated the specific potential of cannabinoids in dampening trigeminal neuropathic pain, data investigating the impact of cannabinoids on BMS, PIFP and PHN is lacking. However, recent data indicate that both CB1 and CB2 are upregulated in tongue epithelia from BMS patients (Borsani et al., 2014) which may aid in identifying cellular markers for BMS pathology. In addition, large bodies of data indicate that cannabinoids target candidate cellular mechanisms underlying BMS, PIFP and PHN pathophysiology. Indeed, cannabinoids alter D1/D2 in the putamen (Dalton and Zavitsanou, 2010) and have characterized effects on TRPV1 (Price et al., 2004) and pro-inflammatory signalling (Downer, 2011) mechanisms in the CNS. In addition, CBR activation can regulate P2X receptor (Krishtal et al., 2006) and 5-HT receptor (Franklin et al., 2013) expression in the CNS, in addition to the well characterized role of CBRs in potassium and calcium ion channel modulation (Pertwee et al., 2010). A body of data indicates that cross-talk between endocannabinoid and opioid systems exists (Scavone et al., 2013), and functional interaction between CB1 and opioid receptors has been reported (Pertwee et al., 2010). Cannabinoids have clear roles in cell death signalling pathways, and neuroprotective roles of cannabinoid ligands are well characterized in the CNS (Pertwee et al., 2010). Finally, cannabinoids alter salivary flow rate (Mattes et al., 1994) and cerebral blood flow (Mathew et al., 2002), which may contribute to the therapeutic potential of cannabinoids in BMS. While cannabinoids have been used in the clinic for several years as anti-emetics, cannabinoid use in pain-related disorders is a promising area of application, particularly given that combination drug therapy may enhance efficacy by targeting multiple pain mechanisms and preclinical studies demonstrate synergism between cannabinoids and opioids (Manzanares et al., 1999). However, obstacles including the absence of a standardized preparation, difficulties in the mode of administration and the existence of adverse effects, have delayed the progress in the clinical development of cannabinoid-based therapies for managing pain. With this in mind, Sativex® currently represents a promising therapeutic avenue for NOP, as this standardized preparation delivers THC and cannabidiol rapidly to the CNS (to act at both CB1 and CB2 ), and demonstrates a good safety and tolerability profile with no evidence of intoxication-like symptoms (Serpell et al., 2012) due to the presence of cannabidiol which is thought to modulate the undesirable effects of THC (Zuardi et al., 2006). Furthermore, Sativex® also offers the advantage of dose titration, which is critical in not only avoiding side effects, but may also improve overall tolerability. In summary, chronic NOP often cannot be satisfactorily treated with conventional analgesics, hence alternative treatment options are sought. Given the well-defined analgesic properties of cannabinoids, in addition to evidence that cannabinoids actively target may pathophysiological mechanisms contributing to NOP disorders, cannabinoids such as Sativex® may represent a bona fide therapeutic strategy for these conditions. Conflict of interest The authors declare that they have no conflict of interest.

Please cite this article in press as: McDonough P, et al. Neuropathic orofacial pain: Cannabinoids as a therapeutic avenue. Int J Biochem Cell Biol (2014), http://dx.doi.org/10.1016/j.biocel.2014.08.007

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Acknowledgements This work was supported by the Center for Drug Discovery, Baylor College of Medicine, the Cork University Dental School and Hospital and the Department of Anatomy and Neuroscience, UCC.

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