5.1. INTRODUCTION

Synthetic and naturally occurring cannabinoids are a focus of strong social, legal, and medical controversy concerning their therapeutic utility, yet studies show that cannabinoids reduce the hyperalgesia and allodynia associated with persistent pain of inflammatory and neuropathic origin in humans and animals. Furthermore, cannabinoids are effective in alleviating chronic pain symptoms after prolonged repeated treatment, unlike opioids, which have only limited effectiveness. A major impediment to the widespread use of cannabinoid analgesics has been their centrally mediated psychotropic side effects. In addition, there are various other conditions where selective activation (or blockade) of peripheral cannabinoid receptors could prove to be of clinical benefit. This chapter will contrast between the peripheral and central actions of cannabinoids to build a case for selective targeting of the peripheral cannabinoid receptors for therapeutic gain.

5.2. CANNABINOID RECEPTORS

The targets of the antinociceptive cannabinoids may be defined by the distribution of two cloned subtypes of cannabinoid receptors, CB1R and CB2R (Matsuda et al. 1990; Munro et al. 1993). These are members of the superfamily of G protein-coupled receptors (GPCRs); both CB1R and CB2R are coupled to G_i/o proteins (Howlett et al. 2002). Another recent addition to the cannabinoid receptor family is the G protein-coupled receptor, GPR55, which couples go G_α11–13 (Begg et al. 2005; Lauckner et al. 2008; Ryberg et al. 2005) (Figure 5.1). CB₁R is actually the most abundant central nervous system (CNS) GPCR expressed at high levels in the hippocampus, cortex, cerebellum, and basal ganglia (Herkenham et al. 1990; Mackie 2005; Matsuda et al. 1990; Tsou et al. 1998). CB1R activation leads to inhibition of adenylyl cyclase (Howlett 1984), blockade of several voltage-gated Ca²⁺-channels (Brown et al. 2004; Guo and Ikeda 2004), and activation of several K⁺-channels (Deadwyler et al. 1995; Felder et al. 1995; Stumpff et al. 2005) (Figure 5.1). There is also some evidence that CB1R activation can block the K⁺ M-current in central neurons (Schweitzer 2000). Central CB1Rs are also localized in regions involved in pain transmission and modulation, specifically in the spinal dorsal horn and periaqueductal gray (Farquhar-Smith et al. 2000; Lichtman et al. 1996; Tsou et al. 1998). In the forebrain, ultrastructural studies have demonstrated a high degree of CB1R localization to presynaptic terminals of cholecystokinin-containing inhibitory interneurons, consistent with the ability of CB1R agonists to decrease evoked release of γ-aminobutyric acid (GABA) (Katona et al. 1999; Tsou et al. 1999). Later studies revealed that presynaptic terminals of glutamatergic fibers in the hippocampus and cerebellum also express CB₁Rs, albeit at much lower levels than in GABAergic neurons (Kawamura et al. 2006). These studies also provided the much needed anatomical basis for the well-known ability of CB1R agonists to decrease excitatory glutamatergic neurotransmission in these brain regions (Ameri et al. 1999; Hoffman et al. 2003; Kreitzer and Regehr 2001; Maejima et al. 2001). In the basal ganglia, CB1Rs are produced in and transported to the terminals of GABAergic medium-sized spiny neurons of the dorsal and ventral striatum (Julian et al. 2003; Matsuda et al. 1993), resulting in a dense CB1R-positive innervation of pallidal and nigral structures (Egertová and Elphick 2000; Katona et al. 1999; Tsou et al. 1998). CB1Rs were also localized to the glutamatergic terminals of corticostriatal neurons (Rodriguez et al. 2001), and functional studies demonstrated that their activation leads to decreased glutamate release from corticostriatal inputs (Gerdeman and Lovinger 2001; Huang et al. 2001). In the brainstem, CB1Rs are expressed at relatively low levels within medullary respiratory control centers (Glass et al. 1997; Herkenham et al. 1990), but are highly expressed in axon terminals within medullary nuclei which control emesis, such as the area postrema (Van Sickle et al. 2001). This distribution is in agreement with the relative lack of respiratory effects and the potent antiemetic actions of cannabinoids (Pertwee 2005a). Since the chemoreceptor trigger zone of the area postrema lies outside the blood-brain barrier, activation of CB1Rs in this area by cannabinoids that do not penetrate the CNS should produce antiemetic actions without CNS side effects.

FIGURE 5.1

Schematic of the four G-protein coupled receptors targeted by endogenous and exogenous cannabinoids/vanilloids and some of their cellular targets. Abbreviations: AC, adenylyl cyclase; Akt, serine/threonine protein kinase; BK, large conductance Ca²⁺-activated (more...)

In the peripheral nervous system, CB1Rs have been detected in dorsal root ganglion (DRG) neurons of heterogeneous size (Salio et al. 2002; Sanudo-Pena et al. 1999), with variable degrees of CB1R mRNA and protein localization to different sensory neuron subtypes. Thus, several groups reported predominant CB₁R localization to large-diameter non-nociceptive neurons (Bridges et al. 2003; Hohmann and Herkenham 1999b; Price et al. 2003), and others localized CB1Rs primarily to small-diameter nociceptors (Ahluwalia et al. 2000; Ahluwalia et al. 2002; Binzen et al. 2006). By contrast, we detected CB1Rs in the majority (89%) of DRG sensory neurons with similar degree of localization in nociceptor and non-nociceptor populations (Mitrirattanakul et al. 2006). Axoplasmic flow of CB1Rs has been demonstrated in peripheral sensory axons, implying transport to terminals where cannabinoids are presumed to produce their antinociceptive effects (Hohmann and Herkenham 1999a). Immunohistochemical studies also revealed CB1R immunoreactivity in both small unmyelinated and large myelinated nerve fiber bundles in the human skin (Ständer et al. 2005). These studies also demonstrated CB1Rs in human macrophages, mast cells, sebaceous cells, and keratinocytes (Ständer et al. 2005). The localization of CB1Rs on the central terminals of primary afferents was controversial for many years, in part because earlier ultrastructural studies failed to detect CB1Rs on these terminals in rats and primates (Farquhar-Smith et al. 2000; Ong and Mackie 1999). However, after detection of CB1Rs on glutamatergic terminals in the hippocampus and cerebellum (Katona et al. 2006; Kawamura et al. 2006), a “re-examination” of the excitatory (glutamatergic) terminals of Aδ- and C-fiber primary afferents in the spinal cord did reveal the presence of CB1Rs on these terminals (Nyilas et al. 2009). These presynaptic CB1Rs likely account for the ability of cannabinoid agonists to decrease the frequency of excitatory postsynaptic currents recorded in spinal cord neurons, thus contributing to the modulation of spinal nociceptive neurotransmission (Morisset et al. 2001).

CB1Rs have also been localized to various neurons of the gastrointestinal (G-I) tract in different species, including humans (Izzo et al. 2001b; Izzo and Coutts 2005). Virtually all cholinergic sensory neurons, interneurons, and motoneurons in myenteric ganglia express CB1R in close association with synaptic protein labeling (Coutts et al. 2002). This differential distribution agrees with the inhibitory actions of cannabinoids on G-I motility and secretion (Izzo et al. 2001b; Izzo and Coutts 2005). Pharmacological studies have also localized CB1Rs to presynaptic terminals of postganglionic sympathetic neurons, where they are thought to mediate depressant effects on sympathetic outflow by inhibiting noradrenaline release (Ishac et al. 1996; Kurz et al. 2008; Niederhoffer et al. 2003; Schultheiss et al. 2005). The presence of CB1Rs was detected in endothelial cells of various vascular beds (Golech et al. 2004a; Rajesh et al. 2007; Sugiura et al. 1998); these likely contribute to the vasodilatory actions of CB1R agonists (Wagner et al. 1998). CB1Rs are expressed in various structures of the human eye (Porcella et al. 2000; Straiker et al. 1999), with particularly high levels of expression in the ciliary body (Porcella et al. 2000). Selective activation of CB1Rs, but not CB2Rs, decreases intraocular pressure (Laine et al. 2003; Oltmanns et al. 2008; Pate et al. 1998; Song and Slowey 2000). However, the precise mechanisms by which cannabinoids decrease intraocular pressure have yet to be elucidated (Tomida et al. 2004). CB1R transcripts are also detected in human spleen, tonsils, and peripheral blood leukocytes, although at levels much lower than those found in the brain (Bouaboula et al. 1993).

By contrast, CB2Rs were initially localized and are most highly expressed by immunocompetent cells of the spleen, thymus, and various circulating immune cell populations (Galiegue et al. 1995; Lynn and Herkenham 1994). While not without controversy, pharmacological studies have suggested, and molecular and immunocytochemical studies have later confirmed, localization of CB2R in both peripheral and CNS neurons (Duncan et al. 2008; Gong et al. 2006; Griffin et al. 1997; Onaivi et al. 2006; Pertwee et al. 1995; Skaper et al. 1996; Ständer et al. 2005; Van Sickle et al. 2005). However, CB2R transcripts in the normal brain are present at much lower levels than CB1R transcripts. It is noteworthy that in contrast to the predominant presynaptic axon terminal location of CB1Rs, CB2Rs appear to localize to the cell bodies and dendrites of central (Gong et al. 2006) and peripheral (Duncan et al. 2008) neurons. Although CB2Rs couple to G_i/o proteins and inhibit adenylyl cyclase, they do not couple to inhibition of voltage-gated Ca²⁺-channels or activation of K⁺-channels (Felder et al. 1995) (Figure 5.1); this may account for the lack of significant psychotropic effects upon administration of CB2R-selective agonists (Hanus et al. 1999; Malan, Jr. et al. 2001). The physiological role of CB2Rs in central neurons is presently unclear; however, administration of CB2R-selective ligands or direct intracerebroventricular administration of CB2R antisense oligonucleotides does modify behavior (Onaivi et al. 2006, 2008). CB2Rs were also localized with CB1Rs to the endothelial cells of human brain capillaries where they were proposed to play a role in regulation of cerebrovascular blood flow and blood-brain barrier permeability (Golech et al. 2004b). In keeping with the immunomodulatory role of CB2Rs, brain and spinal cord microglia (the only hemopoietic lineage cell type in the CNS) are endowed with CB2Rs (Nunez et al. 2004). In addition, GPR55, a novel cannabinoid receptor which is present both in brain and the periphery, may account for some of the actions of cannabinoids by activating signaling pathways quite distinct from those used by CBl/CB2Rs (Ross 2009). The broad expression of the three cannabinoid receptors in the CNS and various visceral organs implies involvement in a variety of physiological processes that are the subject of intensive investigations.

5.3. ENDOCANNABINOIDS AND THEIR METABOLISM

The endogenous lipid cannabinoids that bind to their receptors cannot be sequestered in vesicles and are therefore synthesized on demand and immediately released by neuronal tissues (Di Marzo et al. 1994; Stella et al. 1997). For example, N-arachidonoylethanolamine (anandamide, AEA) is mainly produced by a two-step enzymatic pathway involving calcium-dependent transacylase and phospholipase D (Cadas et al. 1997; Okamoto et al. 2004; Sugiura et al. 1996). Then, AEA either diffuses (Glaser et al. 2003) or is actively transported into cells (Patricelli and Cravatt 2001) and is rapidly degraded by the membrane-bound fatty acid amide hydrolase (FAAH) to arachidonic acid. Another endocannabinoid, 2-arachidonoyl glycerol (2-AG) is synthesized via the diacylglycerol lipase (DAGL)-mediated hydrolysis of diacylglycerol and metabolized primarily by monoacylglycerol lipase (MAGL) (Dinh et al. 2002). There is also evidence that FAAH and two recently characterized serine hydrolases (ABHD6 and ABHD12) may contribute to 2-AG metabolism (Blankman et al. 2007). Interestingly, FAAH is mainly a postsynaptic enzyme, whereas MAGL is localized to presynaptic axon terminals, suggesting possible differences in the functional roles for AEA and 2-AG (Gulyas et al. 2004). The brain levels of 2-AG are at least two orders of magnitude higher than AEA (Stella et al. 1997). Both AEA and 2-AG are cleared by a high-affinity, selective transporter, which has been characterized biochemically but not molecularly (Hillard et al. 2007; Moore et al. 2005). The biochemistry and metabolism of AEA and 2-AG, as well as other less-well-studied endocannabinoids, have been the subject of excellent reviews (Bisogno et al. 2005; Cravatt and Lichtman 2003; Di Marzo et al. 1999; Hillard 2000).

5.4. ENDOCANNABINOIDS AND SYNAPTIC PLASTICITY

The postsynaptic localization of the endocannabinoid production and transport machinery versus the presynaptic location of CB1Rs led to the current and widely accepted view that brain endocannabinoids are synthesized following excitatory activation in postsynaptic neurons yet act as retrograde messengers at presynaptic terminals to decrease the release of various neurotransmitters (Kreitzer and Regehr 2001; Ohno-Shosaku et al. 2001; Wilson and Nicoll 2001). The endocannabinoid-mediated plasticity involves at least four different types of transient and long-lasting synaptic depression, which is found at both excitatory and inhibitory synapses in many different brain regions (Chevaleyre et al. 2006). In addition, endocannabinoids can modify the induction of non-endocannabinoid-mediated forms of synaptic plasticity (Chevaleyre et al. 2006). The widespread involvement of the endocannabinoid system in synaptic plasticity implies a major role in learning and memory and, consequently, behavior. Future studies will be needed to determine specifically how endocannabinoid-mediated synaptic plasticity contributes to modification of behavior.

5.5. ANTINOCICEPTIVE ACTIONS OF CANNABINOIDS

Endocannabinoids such as AEA, naturally occurring Δ⁹-tetrahydrocannabinol (Δ⁹-THC), and synthetic cannabinoids such as WIN 55,212–2 or CP 55,940 inhibit responses to noxious thermal and mechanical stimulation in a variety of tests (Fride and Mechoulam 1993; Lichtman and Martin 1991; Martin et al. 1996; Smith et al. 1994; Sofia et al. 1973; Welch et al. 1998). Blockade of peripheral or central CB1Rs leads to hyperalgesia, suggesting tonic activation of CB1Rs by endocannabinoids (Brusberg et al. 2009; Calignano et al. 1998; Richardson et al. 1997; Strangman et al. 1998). Other studies determined that cannabinoids are also effective in reducing thermal and mechanical hyperalgesia and mechanical allodynia induced by peripheral inflammation (Martin et al. 1999; Richardson et al. 1998a; Richardson et al. 1998b) and peripheral nerve injury in rodents (Herzberg et al. 1997). Similarly, chronic neuropathic pain symptoms in humans are alleviated by cannabinoids (Abrams et al. 2007; Berman et al. 2004; Karst et al. 2003; Notcutt et al. 2004; Nurmikko et al. 2007; Wilsey et al. 2008). Cannabinoids are effective in alleviating neuropathic pain symptoms after prolonged, repeated treatment (Bridges et al. 2001; Costa et al. 2004), unlike opioids, which have only limited effectiveness (Mao et al. 1995; Ossipov et al. 1995; Rashid et al. 2004). The antinociceptive (analgesic) and anti-hyperalgesic effects of cannabinoids were initially thought to be mediated largely by CB1Rs because they are blocked by the selective CB1R antagonist SR 141716A (Calignano et al. 1998; Lichtman and Martin 1997; Richardson et al. 1998b; Rinaldi-Carmona et al. 1994).

5.6. CANNABINOID ACTIONS ON MOTOR CONTROL AND COGNITION

In addition to analgesic effects, acute consumption of cannabis reversibly impairs a variety of cognitive and performance tasks, including memory and learning (Hampson and Deadwyler 1999). Activation of central CB1Rs by cannabinoids such as Δ⁹-THC or AEA produces other complex effects on behavior unique to this class of compounds: at low doses a mixture of stimulatory and depressant effects is observed, and at higher doses central depression predominates (Dewey 1986; Pertwee 1988). Catalepsy, motor deficits, and hypothermia are among the effects observed after administration of centrally acting cannabinoids (Dewey 1986; Maccarrone and Wenger 2005; Pertwee 1988). These properties, which appear in large part mediated by CB1Rs, have greatly limited the clinical use of cannabinoids for the treatment of chronic pain states. At the same time, the increased understanding of CB1R function in the CNS has prompted the evaluation of CB1R ligands for treatment in various other disorders, including psychoses, obesity, multiple sclerosis, stroke, brain trauma, drug addiction, and movement disorders (Basavarajappa and Hungund 2005; Di Marzo and Petrocellis 2006; Mechoulam et al. 2002; Robson 2001).

The synthesis of CB2R-selective agonists such as HU308 and AM1241 was a major development because these compounds produced antinociceptive and antihyperalgesic effects in transient and persistent pain states by activating what was at the time thought to be essentially a peripheral cannabinoid receptor (Hanus et al. 1999; Ibrahim et al. 2003). Importantly, these compounds lack the type of side effects associated with activation of central CB1Rs, which effectively renewed interest in the development of peripherally active cannabinoid-based analgesics.

5.7. ENDOCANNABINOID SYSTEM ALTERATIONS IN INFLAMMATORY AND NEUROPATHIC PAIN STATES

A decade ago it was demonstrated that the antihyperalgesic effectiveness of centrally administered synthetic cannabinoid WIN 55,212–2 is greater after induction of rodent hindpaw inflammation than its antinociceptive effects in non-inflamed hind-paws (Martin et al. 1999). Another study showed that endocannabinoid (AEA) levels in the periaqueductal gray increase in response to peripheral inflammation (Walker et al. 1999). Since then many studies have demonstrated that both CB1Rs and CB2Rs undergo increased expression during inflammation and after development of peripheral nerve injury-induced painful neuropathies (Table 5.1). Such transcription-driven increases in cannabinoid receptors were demonstrated both in the peripheral tissues and the CNS. Increases in the tissue levels of endocannabinoids have also been demonstrated in inflammatory and neuropathic pain states. For example, one study revealed spinal nerve injury-induced increases in the levels of endocannabinoids within sensory ganglia (Mitrirattanakul et al. 2006). Presently it is unknown whether increased endocannabinoid levels are due to their increased “on-demand” synthesis by hyperexcitable neurons or to decreases in the activity of enzymes that metabolize endocannabinoids.

TABLE 5.1

Pathology or Experimentally Induced Alterations in the Endocannabinoid System.

The increases in cannabinoid receptor expression result in increased potency or efficacy of the exogenously applied cannabinoids, depending on whether the ligand is a full (e.g., WIN 55,212–2) or a partial agonist (e.g., Δ⁹-THC) (Pertwee 2008). It is also likely that increased cannabinoid receptor expression contributes to the effectiveness of cannabinoids in providing relief from painful neuropathy symptoms after repeated administration. By contrast, several studies demonstrated that morphine has only limited effectiveness in alleviating peripheral neuropathy symptoms, possibly due to the decreased expression of peripheral opioid receptors (Mao et al. 1995; Ossipov et al. 1995; Rashid et al. 2004). In addition, chronic opioid treatment leads to considerable analgesic tolerance and development of hyperalgesic effects, which together with the well-known respiratory depressant effects have led to the failure of opioid therapy to successfully treat chronic pain populations (see Horvath et al., this volume). By contrast, recent clinical studies have reaffirmed that long-term treatment with cannabinoids for symptomatic relief of peripheral neuropathy symptoms does not result in any appreciable decrement in clinical effectiveness after long-term administration (Nurmikko et al. 2007).

5.8. HOMEOSTATIC ROLE OF THE ENDOCANNABINOID SYSTEM

In addition to inflammatory and neuropathic pain states, it appears that any pathological condition that involves an inflammatory response, whether generated from an injury, a foreign organism, or the autoimmune system, results in the up-regulation of the endocannabinoid system. Thus, alterations (usually increases) in cannabinoid receptors and/or their endogenous ligands have been observed in temporal lobe epilepsy (Wallace et al. 2003), alcohol withdrawal and dependence (Mitrirattanakul et al. 2007), brain ischemia (Jin et al. 2000), endometritis (Iuvone et al. 2008), pancreatitis (Michalski et al. 2007), and various other types of injury (Table 5.1). Also, injury symptomatology is exacerbated in the presence of CB1R or CB2R antagonists or in mice with genetic deletions of CB1R and CB2R (Baker et al. 2000; Batkai et al. 2007; Kimball et al. 2006; Massa et al. 2004; Palazuelos et al. 2008; Panikashvili et al. 2005; Schuelert and McDougall 2008). While the specific alterations appear to depend on the type of injury/pathology, an overall emerging view is that the up-regulation of the endocannabinoid system is the organism’s compensatory mechanism designed to alleviate the negative consequences of tissue injury and facilitate repair (Di Marzo and Petrocellis 2006; Mechoulam and Shohami 2007; Pertwee 2005b). Nevertheless, there are several clinically relevant situations where increases in CB1R expression may have an adverse effect. In these conditions, selective blockade of peripheral CB1Rs could prove to be of clinical benefit (Kunos et al. 2009). Also, mice with a genetic deletion of GPR55 were recently shown not to develop either inflammatory- or nerve injury-induced hyperalgesia, suggesting that selective GPR55 antagonists may also be of utility for treating inflammatory or neuropathic pain (Staton et al. 2008).

5.9. ACTIONS AT NON-CANNABINOID RECEPTORS

In addition to the diverse physiological effects of cannabinoid receptor activation, certain cannabinoids have effects at other targets. For example, anandamide administration in CB1R -/- mice still produces cannabinomimetic effects in various behavioral tests (Baskfield et al. 2004; Di Marzo et al. 2000a). Although some of these effects could be ascribed to actions at CB2Rs or GPR55Rs, others may be due to activation of non-cannabinoid receptors or to receptor-independent interactions with membrane ion channels and intracellular second-messenger systems (Oz 2006). In particular, several endogenous and synthetic cannabinoids have demonstrated effects at transient receptor potential (TRP) receptors. Certain TRP receptors (e.g., TRPV1) are highly expressed in nociceptors where they play an important role in detection of nociceptive signals and nociceptor sensitization in inflammatory and neuropathic pain states (Tominaga and Caterina 2004).

Several studies demonstrated that near physiological concentrations of AEA produce local vasodilation (Zygmunt et al. 1999), vas deferens relaxation (Ross et al. 2001), and excitation of the central terminals of sensory afferents (Tognetto et al. 2001), all via TRPV1 receptor activation. Such studies led to the idea that endocannabinoids acting via TRPV1 may contribute to nociception and hyperalgesia, reviewed by Di Marzo et al. (2001a) and Szolcsanyi (2000). Indeed, AEA was implicated in the inflammatory response of certain tissues. Thus, toxin A-induced inflammation and edema of the ileum was shown to be dependent on activation of TRPV1 receptors by endogenous AEA (McVey et al. 2003). Similar findings were obtained in cyclophosphamide-induced bladder hyperreflexia and cystitis (Dinis et al. 2004). It was also shown that inflammatory mediators can convert anandamide into a potent activator of TRPV1 receptors, possibly via receptor sensitization (Singh Tahim et al. 2005). On the other hand, many studies showed that cannabinoids require micromolar levels to activate TRP receptors, whereas activation of antinociceptive cannabinoid receptors occurs at nanomolar levels. Thus, with the possible exception of N-arachidonoyl dopamine (nm activation of TRPV1 receptors [Huang et al. 2002]), both endogenous and exogenous cannabinoids that possess TRP activity act as partial agonists at TRP receptors (Akopian et al. 2008; Nemeth et al. 2003; Roberts et al. 2002; Ross 2003). In addition, cannabinoid receptor-mediated activation of calcineurin results in TRPV1 receptor desensitization (Jeske et al. 2006; Patwardhan et al. 2006). Recent studies have also demonstrated that selective activation of CB2Rs on human sensory neurons blocks capsaicin-induced inward currents and cytoplasmic Ca²⁺ elevation via inhibition of adenylyl cyclase (Anand et al. 2008). Collectively, these studies help explain why exogenous cannabinoids produce analgesic and anti-hyperalgesic effects rather than pronociceptive effects after local peripheral or systemic administration.

5.10. DISSOCIATING EFFECTS OF PERIPHERAL AND CENTRAL CANNABINOID RECEPTOR ACTIVATION

Early studies have assumed a central action of cannabinoids based on the high degree of CB1R expression in the brain, including various sites associated with pain signal transmission and modulation. Subsequently, multiple studies with genetically engineered mice lacking CB1Rs have confirmed their role in cannabinoid-induced analgesia (Ledent et al. 1999; Zimmer et al. 1999) but did not localize their actions to peripheral or central receptors. Evidence for important peripheral sites of cannabinoid analgesic effects came from studies where local administration of cannabinoids into inflamed tissue attenuated hyperalgesia and allodynia via peripheral CB1Rs, at doses that produced minimal centrally mediated side effects (Amaya et al. 2006; Gutierrez et al. 2007; Richardson et al. 1998b). Peripheral CB1R activation was also shown to reduce mechanical activation of A-δ nociceptors from inflamed skin but not from non-inflamed skin (Potenzieri et al. 2008a). Similarly, local activation of peripheral CB1Rs attenuates hyperalgesia produced by thermal injury (Johanek and Simone 2004), nerve injury (Fox et al. 2001), and cancer (Guerrero et al. 2008; Potenzieri et al. 2008b). However, the crucial role of peripheral cannabinoid receptors in the antihyperalgesic actions of systemically administered cannabinoids was demonstrated only recently using conditional deletion of CB1Rs located on nociceptive primary afferent neurons (Agarwal et al. 2007). In these conditional peripheral CB1R knockout mice, the antihyperalgesic effects of systemically administered cannabinoids were nearly completely lost in models of carrageenan-induced inflammation and sciatic nerve injury-induced neuropathy. By contrast, the effects of central CB1R activation were retained in the conditional knockouts but lost in the global CB1R-null mice (Agarwal et al. 2007).

5.11. STRATEGIES FOR PERIPHERAL CANNABINOID RECEPTOR TARGETING

Considerable experimental and clinical evidence points to the homeostatic role of the endocannabinoid system in ameliorating the negative consequences of tissue injury. Therapeutic targeting of the peripheral cannabinoid receptors could provide relief of injury symptoms and speed up tissue repair, while minimizing the side-effects associated with activation of central cannabinoid receptors.

One approach already taken was the development of CB2R-selective ligands. Given the recent demonstrations of CB2Rs on human sensory nerve fibers (Anand et al. 2008; Ständer et al. 2005) and the increased expression of CB2Rs within human and rat sensory neurons after inflammation and peripheral nerve injury (Anand et al. 2008; Beltramo et al. 2006; Wotherspoon et al. 2005), CB2R-selective agonists promise to become an important treatment option for inflammatory and neuropathic pain states (Guindon and Hohmann 2008). CB2R-selective agonists are also being considered for the treatment of myocardial ischemia and atherosclerosis (Pacher et al. 2008). In addition, CB2R-selective antagonists may be of value in the treatment of certain degenerative bone diseases such as rheumatoid arthritis (Lunn et al. 2007). Many CB2R-selective ligands have been developed (Huffman 2000; Huffman et al. 2002), although brain-impermeant analogues are not being emphasized because of the limited localization of CB2Rs in the CNS under normal conditions (Ibrahim et al. 2003), as well as their increased central expression in neuropathic pain states (Beltramo et al. 2006; Zhang et al. 2003) and in autoimmune disorders (Benito et al. 2008). A potential concern with administration of CB2R agonists for the treatment of chronic pain symptoms is excessive suppression of the immune system, which could make them unsuitable as therapeutics in patients with compromised immune systems.

One alternative strategy might be to develop selective CB1R agonists that do not penetrate the blood-brain barrier, thereby providing pain relief without the side effects associated with central CB1R activation. Indeed, one compound with a dual CB1R/CB2R agonist profile (~170-fold preference for CB1R over CB2R) and restricted CNS permeability was recently shown to possess antihyperalgesic properties without appreciable central side effects (Dziadulewicz et al. 2007). Another study demonstrated this compound’s effectiveness against colorectal distention-induced visceral pain; this action was blocked by CB1R but not CB2R antagonists (Brusberg et al. 2009). Several other CB1R ligands were suggested to exhibit limited brain penetration and few psychotropic side effects (Fride et al. 2004). However, some derivatives turned out to have little activity at CB1Rs or CB2Rs; their effects appear to be mediated through other mechanisms yet to be defined (Pertwee et al. 2005). Other new derivatives may bind CB1Rs but may exhibit antagonistic activity at these receptors (Ben-Shabat et al. 2006). Thus, development of peripherally acting CB1R-selective agonists continues to represent an important goal. Such brain-impermeant analgesics would still be expected to produce side effects of peripheral CB1R activation such as constipation, hypotension, and possibly weight gain. There is also a potential concern for the development of tolerance to CB1R agonists during prolonged treatment. However, in recent clinical trials of cannabis preparations for neuropathic pain treatment, such side effects were well tolerated and there was no evidence for development of analgesic tolerance with long-term treatment (Ellis et al. 2009; Nurmikko et al. 2007; Wilsey et al. 2008).

Peripherally acting CB1R-selective analgesics are unlikely to replace non-steroidal anti-inflammatory analgesics (NSAlAs) and opioids as the mainstay treatment for acute or postoperative pain. Indeed, several studies demonstrated the relatively poor response of cannabinoids in postoperative pain relief (Beaulieu 2006; Buggy et al. 2003). However, CB1R-selective analgesics may be a panacea for the treatment of various types of chronic pain in situations where NSAIAs or opioids may be contraindicated. For example, patients with G-I ulcers treated with CB1R agonists could benefit from the demonstrated antiulcer effects of cannabinoids (Izzo et al. 2001b). Similarly, asthmatic patients could benefit from the bronchodilator properties of cannabinoids (Gong, Jr. et al. 1984), which are not dependent on prostaglandins (Laviolette and Belanger 1986).

Other therapeutic applications where selective activation of peripheral CB1Rs could prove useful include (1) decreasing intraocular pressure in glaucoma resistant to conventional therapies (Porcella et al. 2001); (2) antiemetic actions via CB1R activation in area postrema, which are located outside the blood-brain barrier (Machado Rocha et al. 2008); (3) antidiarrheal actions (Esfandyari et al. 2007); (4) antitumorigenic actions (Ligresti et al. 2006); and (5) treatment of bone diseases associated with accelerated osteoclastic bone resorption including osteoporosis, rheumatoid arthritis, and bone metastasis (Idris 2008).

Alternatively, there are several conditions where selective blockade of peripheral CB1Rs would be desirable to prevent the anxiety and depression symptoms associated with blockade of central CB1Rs (Christensen et al. 2007). These conditions, which have been the subject of recent reviews, include metabolic and vascular regulation in obesity, hepatic steatosis of various origins, and treatment of dyslipidimeas and insulin resistance (Kunos et al. 2009; Magen et al. 2008; Sarzani 2008). Also, development of peripherally acting selective blockers of GPR55 may prove useful for the treatment of chronic pain states given the recent demonstration of a non-hyperalgesic phenotype of GPR55-null mice after peripheral nerve injury or inflammation (Staton et al. 2008).

Another option is to develop peripherally acting selective inhibitors of endocannabinoid metabolism to elevate endocannabinoid levels, which would result in increased activation of both CB1Rs and CB2Rs. An important advantage of such metabolism inhibitors over CB1R or CB2R agonists is that increases in endocannabinoid levels would be achieved at the physiological sites of endocannabinoid production and release. Indeed, selective FAAH inhibitors have already been developed (Kathuria et al. 2003) and demonstrated to ameliorate neuropathic pain symptoms (Lichtman et al. 2004). Inhibitors of MAGL have also been developed (Ghafouri et al. 2004; Quistad et al. 2006). To our knowledge, these FAAH and MAGL inhibitors are all brain-permeable (Bisogno et al. 2006; Ghafouri et al. 2004; Karbarz et al. 2009; Kathuria et al. 2003; Lichtman et al. 2004; Makara et al. 2005; Minkkila et al. 2009; Myllymaki et al. 2007; Quistad et al. 2006). It is noteworthy that despite CNS permeability, these inhibitors do not appear to exhibit the adverse side effects of central CB1R activation (Comelli et al. 2007; Esfandyari et al. 2007; Kathuria et al. 2003). Also, new selective inhibitors of anandamide uptake have recently been synthesized (Ortar et al. 2008). Unlike their parent compound (Moore et al. 2005), these inhibitors have no appreciable effects on FAAH or MAGL activity (Ortar et al. 2008). The physiological consequences of selective AEA uptake inhibition have yet to be determined, but if it results in elevated AEA levels, it could prove to be an important addition to cannabinoid-based therapeutics.

5.12. FUTURE PROSPECTS

Selective activation of peripheral CB1Rs brings the promise of completely dissociating the antinociceptive and antihyperalgesic effects of cannabinoids from their centrally mediated psychotropic side effects. Similarly, restricting CB1R blockers to the periphery would dissociate anxiogenic and depressant side effects of such blockers from their therapeutic actions. Various academic institutions and the pharmaceutical industry are currently pursuing the development of orally bioavailable, brain-impermeable cannabinoid receptor ligands. Even if such centrally impermeant drugs do not become a mainstay of clinical pharmacology, they should be useful tools in unraveling the complexities of the endlessly fascinating endocannabinoid system.

ACKNOWLEDGMENT

Support contributed by NIH grants AA016100 and DA023163.

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