Cannabinoids modulate pain by multiple mechanisms of action

Cannabinoids Modulate Pain by Multiple Mechanisms of Action Jennelle Durnett Richardson Abstract:

Historically, the evidence for cannabinoids acting as analgesics has been mostly anecdotal. Recently, studies utilizing animal models have indicated that cannabinoids produce antinociception and antihyperalgesia by acting at peripheral, spinal, and supraspinal sites to inhibit mast cell degranulation, primary afferent activity, and responses of nociceptive neurons. Additionally, a number of studies indicate that the cannabinoid system tonically regulates nociceptive thresholds, raising the possibility that hypoactivity of the cannabinoid system produces or prolongs hyperalgesia and chronic pain. Other studies have indicated that inactive doses of cannabinoids potentiate the antinociceptive effects of opioids. Collectively, these studies suggest that administration of peripherally selective cannabinoids, enhancement of endogenous cannabinoid activity, and coadministration of inactive doses of cannabinoids with other analgesics, such as morphine, may prove therapeutically beneficial and may also provide ways to separate the analgesic effects of cannabinoids from their side effects. Key words:

Cannabinoid,

analgesia,

nociception,

annabinoids have been used therapeutically for millennia. Traces of Ag-tetrahydrocannabinol (Ag-THC),the psychoactivscomponent of marijuana, have been found in Egyptian mummies from as early as 950 6C.l Peoples in the Middle East, India, and China have used cannabinoids as analgesics, anticonvulsants, antispasmodics, antiemetics, and hypnotics.* Before its classification as a narcotic in the nineteenth century, marijuana also was widely used in the United States for medicinal purposes. Today, Ag-THC is classified as a Schedule I drug, which has made it more difficult to conduct the controlled human studies necessary to evaluate its effectiveness. Nonetheless, there have been human studies that have evaluated the analgesic properties of cannabinoids. Controlled human studies evaluating the effectiveness of cannabinoid agonists have indicated that they will produce analgesia (Table 1).

C

From the Department of Neurobiology, Harvard Medical School, Boston, MA. Supported in part by the Howard Hughes Medical Institute and the Edward R. and Anne G. Lefler Center. Address reprint requests to Jennelle Durnett Richardson, PhD, Department of Neurobiology, Harvard Medical School, Boston, MA 02115. E-mail: [email protected] 0 2000 by the American Pain Society 1526-5900/00/0101-0002$5.00/O

2

hyperalgesia,

endogenous.

However, some of these studies suggest that they may be limited in usage because of either their side effects or a lack of clear benefit over currently available analgesics. It should be noted that it is difficult to generalize from these studies on the effectiveness of cannabinoids as analgesics for 3 reasons. First, not all of the studies were conducted in a double-blind fashion because of limitations of the experimental design (ie, either too few patients or a survey of patients). Second, oral absorption of Ag-THC is slow and erratic; thus, it may not fully reflect cannabinoid effects.3 Third, these studies were conducted on a variety of pain states. Because different types of pain can respond differently to the same drugs, cannabinoids may be less effective in treating some types of pain than others. For example, cannabinoids were more effective in treating pain caused by spinal cord injury than in treating pain caused by cancer.4,5 Additionally, side effects did not preclude the use of cannabinoids in patients with spinal cord injury or muscle pain from multiple sclerosis, but were limiting in patients with advanced cancer and in postoperative patients. 4-8 Although an analgesic role for cannabinoids is suggested from these studies, more studies need to be conducted to better evaluate the cannabinoid effects on these and other pain states.

The Journal of Pain, Vol 1, No 1 (Spring), 2000: pp 2-14

CRITICAL REVIEW/Richardson Table

I.

3

ClinicalStudiesof the AnalgesicEffectsof Cannabinoids

DRUG

ROUTE

DOSE

Dg-THC

20 mg

Levonantradol

1.5-3

Ag-THC

5 mg

p.0.

Nabilone

1 mg

p.0.

Marijuana

3 times per day

Smoked

Marijuana

3 times per day

Smoked

Abbreviations:

po.,

p.0. mg

i.m.

SUBJECTS

ANALGESIA?

34 advanced cancer patients 56 acute postoperative patients 1 patient with spinal cord injury 1 multiple sclerosis patient with muscle pain 112 multiple sclerosis patients surveyed about chronic muscle pain 112 multiple sclerosis patients surveyed about trigeminal neuralgia

Similar to 120 mg codeine Significant compared to placebo Similar to 50 mg codeine Yes

COMMON SIDE EFFECTS

REFERENCE

Sedation, drowsiness Drowsiness

7

None

reported

4 8

Yes

Brief, mild sedation None reported

Yes

None

6

reported

5

6

oral; i.m., intramuscular.

Because of the difficulties in conducting clinical trials with cannabinoids, ranging from the lack of cannabinoids that are well-absorbed orally to overcoming the stigma associated with the use of cannabinoids, animal studies have been particularly useful in evaluating the role of cannabinoids in modulating nociception. A number of advances in the cannabinoid field over the last few decades have facilitated these studies. Collectively, the studies indicate that (1) cannabinoids produce antinociceptive and antihyperalgesic effects at peripheral, spinal, and supraspinal sites, which may be taken advantage of therapeutically to avoid systemic administration and subsequentside effects; (2) tonic activity of the cannabinoid receptors modulates nociceptive thresholds and may play a role in the etiology of chronic pain states; and (3) cannabinoids and opioids can potentiate one another’s effects, suggesting that their combination may be useful therapeutically to provide greater analgesia and avoid side effects.

Pharmacologyof Cannabinoids The psychoactive component of marijuana was identified as Ag-THC in the mid-1960s.g This prompted research that focused on understanding the structure-activity relationships of cannabinoids, which led to the development of a number of synthetic cannabinoids. The cannabinoid agonists are traditionally divided into 3 families: classical agonists such as Ag-THC; nonclassical agonists, such as CP 55,940; and aminoalkylindole agonists, such as WIN 55,212. The family was expanded with the recent identification of the endogenous cannabinoid anandamide.lO Since then, other fatty acid ethanolamides and fatty acid esters that act as endogenous cannabinoids have been discovered.l’-l3

The mechanisms of synthesis, release, and degradation of the endogenous cannabinoids have been the focus of much recent research. Endogenous cannabinoid precursors are formed from membrane phosphatidylcholines and are then cleaved by various phosphodiesterases to form the family of fatty acid ethanolamines and fatty acid esters that act as endogenous cannabinoids.14,15 The synthesis of the endogenous cannabinoids is calcium-dependent and can be potentiated with concurrent activation of CAMP (cyclic adenosine monophosphate)dependent protein kinase.16-‘* The cannabinoids are thought to be synthesized and released on demand. They are removed from the cleft by facilitated transport. lg-*l Once inside the cell, the endogenous cannabinoids are degraded by the recently identified enzyme fatty acid amide hydrolase (FAAH) into their respective fatty acids and ethanolamine or ester.20,22-27 These can then be reincorporated into phospholipids. In addition to endogenous agonists,. some fatty acid esters are themselves ineffective as cannabinoid agonists, but can potentiate the effects of endogenous cannabinoids.28 This is thought to occur by multiple mechanisms, one of which being the inhibition of the breakdown of the endogenous cannabinoid, presumably by competing at the FAAH. In the synaptic cleft the cannabinoids interact selectively with cannabinoid receptors leading to a multitude of effects. Two cannabinoid receptors have been identified to date. The CB, receptor has been found primarily in the central nervous system, whereas the CB, receptor has been reported almost exclusively in the periphery.2g-31 Additionally, a splice variant of the CB, receptor (CB,,) has been cloned that differs from the CB, receptor

4

Table

Cannabinoids

2.

ROUTE

CANNASINOIO

Ag-THC

REFERENCE

CB, or CB, CB, or CB, W

108 109 100

i.v. S.C. i.m.

CB, or CB, CB, or CB,

70 108 101

p.0. i.p.

CB, CB,

i.v.

CB,

i.v.

CB, or’CB,

p.0. i.p.

Anandamide WIN 55, 212-2 Levonantradol WIN

RECEPTOR ACTIVATED

S.C.

Levonantradol Ag-THC

Ag-THC

Thermal

Pain

AntinociceptiveEffectsof Cannabinoids

NOXIOUS S~~fduLus Mechanical

Modulate

CB,

55, 212-2

Ag-THC Ag-THC

or CB, or CB,

109 110,111

Anandamide

Ag7HC WIN

45.48

55, 212-2

Ag-THC

59, 70, 82, 111,112

WIN 55, 212-2 CP 55, 940 Anandamide Ag-THC WIN 55, 212-2 CP 55, 940 WIN 55, 212-2 CP 55, 940 WIN 55, 212-2

i.c.v.

into

PAG

Into dorsal nucleus into RVM i.t. i.t.

WIN 55, 212-2 Levonantradol

Ag-THC

raphe

CB,

113-115

CB,?

80,

113

CB,?

80

93

CB,

CB, or CB, CB, or CB,

116 82,84,111

WIN 55, 212-2 CP 55, 940 Anandamide Abbreviations:

s.c., subcutaneous;

i.p., intraperitoneal;

i.v., intravenous;

i.m., intramuscular;

at the amino terminal.32 Activation of either receptor will result in the inhibition of adenylyl cyclase activity by a G,, protein.30,33-35 Activation of the CB,, but not CB,, receptor also will inactivate potassium A currents, activate Gprotein-coupled, inwardly rectifying potassium channels; inhibit calcium channel activity; and activate mitogen-activated protein kinase.34,36-43 The majority of the cannabinoid agonists do not show selectivity for CB, or CB, receptors.34 One exception to this is the endogenous cannabinoid palmitoylethanolamide (PEA), which is selective for the CB, receptor. 44 The best characterized selective CB, receptor antagonist is SR 14171 6A.45 Recently, reports have emerged that SR 141716A and other CB, receptor antagonists can produce effects opposite of cannabinoid agonists when administered by themselves.46-68 This suggests that either endogenous cannabinoids are active in these systems, or the CB, receptor is tonically active and SR 141716A is functioning as an inverse agonist to negatively modulate receptor activity. In support of the lat-

i.c.v., intracerebroventricular;

i.t., intrathecal;

p.o., oral

ter, there is evidence that the CB, receptor is capable of tonic activity in both transfected cells and cells that endogenously express the CB, receptor.46,60 Studies also indicate that the selective CB, receptor antagonist SR 144528 can function as an inverse agonist.62,6g For the sake of simplicity, the compounds will be referred to as antagonists in this review. The identification of Ag-THC, the development of synthetic cannabinoids and cannabinoid receptor antagonists, and the discovery of endogenous cannabinoids have facilitated the evaluation of the involvement of cannabinoids in nociceptive transmission.

Effects of ExogenouslyAdministered Cannabinoids The classical effects of administration of cannabinoids include antinociception, hypothermia, hypomotility, and catalepsy. One concern has been that the temperature and motor effects could influence an animal’s responsiveness in antinociceptive tests. However, there is no effect

CRITICAL REVIEW/Richardson Table

3.

5

AntihyperalgesicEffectsof Cannabinoids

MODEL

CANNA~YNOID

ROUTE

Carrageenan

Anandamide Anandamide PEA Ay-THC CP 55,940 CP 55,940 WIN 55,212-2 WIN 55,212-2 Anandamide Anandamide PEA PEA WIN 55,212-2 WIN 55,212-2 PEA Anandamide

i.pl. i.t. p.0. p.0. i.pl. i.pl. i.p. i.pl. i.p. i.pl. i.p. i.pl. i.p. i.p. i.a. i.a.

Yeast Capsaicin Formalin

ccl Bladder

inflammation

Abbreviations:

i.pl., intrapiantar;

i.t., intrathecal;

i.p., intraperitoneal;

RECEPTOR ACTIVATED CB, CB,? ‘ B* CB, CB, CB, CB,

CB, CB, CB, CB,

Thermal Thermal Mechanical Mechanical Thermal Mechanical

‘B, CB, or CB, CB, ‘B, 3 CB, CB, ‘% CB, or CB,

i.a., intra-auricular;

of systemic administration of WIN 55,212-2 on paw or tail skin temperatures at antinociceptive doses.70 Additionally, there is a temporal separation of the motor and antinociceptive effects, indicating that the cannabinoid-induced temperature and motor changes are distinct from the antinociceptive effects. 7o Furthermore, electrophysiological recordings after systemic administration of WIN 55,212-2 have revealed a selective effect on noxious stimulus-evoked neuronal firing that has been correlated with the antinociception.70-72 The separation of antinociceptive, temperature, and motor effects, the ability of cannabinoids to selectively affect firing in response to noxious stimuli, and the correlation of the effects on nociceptive neuronal firing with behavioral antinociception support an effect of cannabinoids on nociceptive processing. The distribution of cannabinoid receptors also supports a role for cannabinoids in nociceptive processing. The CB, receptors, which primarily have a peripheral distribution, have been identified on mast cells and have been shown to inhibit mast cell degranulation.44 CB, receptors, which have been identified both peripherally and centrally, are expressed in a number of regions involved in nociceptive processing. Cannabinoid binding sites have been identified in the trigeminal ganglion and CB,, but not in CB,. Receptor messenger RNA (mRNA) is expressed in the dorsal root ganglion (DRG).73-75 The CB, receptor is then transported both peripherally and centrally as indicated by sciatic nerve ligation, dorsal rhizotomy, and neonatal capsaicin studies.73,76,77 A small percentage of the CB, mRNA-positive DRG cells also express substance P or calcitonin gene-related peptide

or or or or

Noxious STIMULUS

Thermal Mechanical Mechanical Mechanical

REFERENCE 96 75 95 109 97 97 98 47 94 47 94 47 55 55 94 94

p.0.. oral.

(CGRP) mRNA, whereas the majority of the Cyd mRNA is expressed in fibers of larger diameter. Binding studies in the spinal cord using the nonselective cannabinoid receptor agonist [3H]CP 55,940 have identified cannabinoid binding sites in the dorsal horn.78 This binding probably represents CB, receptors because CB, receptors have not been identified in the DRG or central nervous system (CNS), a selective CB, receptor antagonist showed a similar concentration of binding sites in the dorsal horn, and a similar spinal distribution was observed with an antibody directed against CB, receptors.31,64,73,7g Based on the neonatal capsaicin and dorsal rhizotomy studies, these spinal cannabinoid binding sites are located on capsaicin-sensitive and large diameter primary afferent fibers as well as nonprimary afferent fibers.76,77 Supraspinally, cannabinoid binding sites have been identified in periaquaductal gray (PAG) and dorsal raphe nucleus.78,80 These sites probably represent CB, receptors because CB, receptor mRNA has not been identified in brain and because CB,-like immunoreactivity has also been detected in the PAG.31,7gThese studies suggest that cannabinoids may modulate nociceptive thresholds by interacting with receptors in various regions recognized to have a role in nociceptive transmission. Administration of cannabinoids to normal animals produces both thermal and mechanical antinociception via the CB, receptor. Table 2 reviews antinociceptive effects of prototype cannabinoid compounds. Anatomic studies, local administration, and studies in spinalized animals indicate that this antinociception is mediated both spinally and supraspinally.81-83 There are a number of potential mechanisms by which

6 Table

Cannabinoids

Modulate

Pain

4. Effects of CB Receptor Antagonists

ROUTE

NOXIOUS STIMULUS

SR 141716A SR 141716A SR 141716A SR 141716A SR 141716A Antisense to CB,

i.m. p.0.; i.p. i.p. i.v. i.t. i.t.

CB, CB, CB, CB, CB, CB,

SR 141716A SR 141716A SR 141716A SR 141716A SR 144528 SR 141716A SR141716A

i.pl. i.p. i.v. i.pl. i.v. i.p. i.p.

CB, CB, CB, CB, -2 -1 CB,

Thermal Thermal Mechanical Thermal Thermal Thermal Thermal Mechanical Thermal

MODEL

Normal

DRUG

Knockout Carrageenan Formalin

CCI Abbreviations:

ENHANCED HYPERALGESIA/ ALLODYNIA?

RECEPTOR INHIBITED

i.m., intramuscular;

i.p., intraperitoneal,

iv., intravenous;

cannabinoids may produce antinociception in the spinal cord. Cannabinoids can act at spinal CB, receptors to inhibit capsaicin-sensitive fibers in lumbar dorsal horn slices and to decrease noxious stimulus-evoked firing of wide dynamic range (WDR) neurons. 75,84There is also evidence that activation of the spinal CB, receptor can decrease NMDA receptor activation potentially by inhibiting glutamate release into the spinal cord.64,85 Furthermore, it appears that cannabinoids may modulate spinal noradrenergic and cannabinoids opioid systems. 86-g2 Supraspinally, might also modulate opioid systems.8g,g0 Additionally, cannabinoids have been shown to decrease noxious stimulus-evoked firing of nociceptive neurons in the ventroposterolateral nucleus of the thalamus as well as in the rostra1 ventromedial medulla (RVM) with the latter being a demonstrated CB, receptor effect.5g~70,g3 In the RVM, cannabinoids eliminate the “off” cell pause as well as the “on” cell burst that occur just before the tail-flick withdrawal reflex. Finally, both systemic and intracerebroventricular (i.c.v.) administration of cannabinoids have been shown to decrease noxious-heat evoked activity of WDR neurons in a manner sensitive to spinalization, indicating a supraspinal site of action of cannabinoids and descending modulation of WDR neurons.72 Together, these studies indicate that cannabinoids can act both spinally and supraspinally to decrease nociceptive responsiveness of neurons and that the supraspinal effects might result in descending modulatory control of spinal nociception. In addition to evaluating the effect of cannabinoids on nociceptive thresholds of normal animals, it is also important to evaluate their effects

i.t., intrathecal;

Thermal Mechanical i.pl., intraplantar;

No No No Ye5 Yes Yes No No No Yes Yes Yes Ye5 Yes Yes

REFERENCE

101 45 100 59 64 64 102,103 102 96 66 47 47 47 55 55

p.o., oral.

during conditions of hyperalgesia. Effects of drugs during hyperalgesia most closely approximate therapeutic situations. Furthermore, different pain states probably have different etiologies. Thus, the mechanism of action, potency, and efficacy of cannabinoids might differ between normal and hyperalgesic conditions as well as between hyperalgesic conditions of different etiologies. These differences may lead us to a better understanding of the cannabinoids as well as elucidate potential involvement of cannabinoids in the etiology of different pain conditions. Administration of cannabinoids will produce antihyperalgesia in a number of animal models (Table 3). This is mediated both at peripheral and central sites. The CB, selective agonist PEA has been administered both systemically and locally into the hindpaw and will produce antihyperalgesia in the carrageenan, formalin, and bladder inflammation models and reduce carrageenan-, formalin-, and dextran-induced edema.g4,g5 This effect is peripheral because there is a loss of potency when PEA is administered systemically.47 Because CB, receptors appear to be absent from primary afferent fibers but are present in mast cells and down-modulate mast cell activation in vitro, the effect of PEA is thought to be mediated by the inhibition of mast cell degranulation.44,73 Indeed, after systemic administration, PEA inhibited substance P-induced mast cell degranulation and plasma extravasation.g5 The activation of peripheral CB, receptors also might contribute to antihyperalgesia as indicated by the local administration of nonselective agonists and the reversal of effects with a selective CB, receptor antagonist. 47,g6 The CB, receptor also has been shown to mediate cannabinoid-induced

CRITICAL

REVIEW/Richardson

Table

5.

ACTIVE

OR

INACTIVE

Effectsof Coadministrationof Ag-THC and p Opioid ReceptorAgonists

DOSE

OF Ag-THC

7

ACTIVE

Ag-THC ROUTE

Inactive Inactive Active Active Inactive

S.C. p.0.

INACTIVE

OR DOSE

BLOCK OP/O/D

OF w oP/O/O

ROUTE

ENHANCED ANTINOCICEPTION?

s.c.; p.0. 5.c.; p.0. i.p.

i.v.

Active Active Inactive Inactive Inactive

i.p.

Yes Yes Yes Yes Yes

Inactive Inactive inactive

i.v. i.t. i.t.

Inactive Active Active

i.c.v. i.t. Lt.

Yes Yes Yes

inactive

i.t.

Active

Lt.

Yes

Inactive

it.

Active

i.t

Yes

Abbreviations:

i.v. S.C.

s.c., subcutaneous;

p.0.. oral; i.v., intravenous;

S.C.

i.t., intrathecal;

inhibition of plasma extravasation.g6 These effects are peripheral because of a decreased effectiveness when administering the drug systemically or contralaterally as well as the finding that 94% of [3H]anandamide remained in the paw 10 minutes after an intraplantar (i.pl.) injection.47,g6,g7 A potential mechanism for CB,-mediated antihyperalgesia in the periphery is the inhibition of neuropeptide release from capsaicinsensitive primary afferent fibers.g6 Additionally, because activation of the CB, receptor enhances certain potassium channel activity, postsynaptic membranes may be stabilized at subthreshold potentials, making them more difficult to activate. An interaction of cannabinoids with receptors on primary afferent fibers is consistent with studies showing colocalization of the CB., receptor and CGRP in a subpopulation of DRG cells.74 As mentioned above, cannabinoids also can act at central terminals of capsaicin-sensitive primary afferent fibers to inhibit neuropeptide release.75 Additionally, systemic administration of WIN 55,212-2 suppressed formalin-induced c-fos expression in laminae l/II and VA/I of the spinal cord but not in the non-nociceptive III/IV laminae.g8 The other mechanisms postulated to underlie spinal and supraspinal antinociception also might be involved in mediating antihyperalgesia. Together, these results show peripheral and central mechanisms that might mediate the antihyperalgesic effects of cannabinoids. Collectively, these anatomic, behavioral, neurochemical, and electrophysiological studies support a role for peripheral, spinal, and supraspinal regions in modulating nociceptive thresholds. Peripherally, cannabinoids interact with CB, receptors on primary afferent fibers to inhibit activation as well as CB, receptors on mast cells

i.c.v., intracerebroventricular;

ENHANCEMENT WITH:

REFERENCE

i.c.v. B-funaltrexamine; i.t. nor-BNI i.t. nor-BNI i.t. anti-sera dynorphin i.t. anti-sera dynorphin i.t. anti-sera dynorphin

to (1-B) to (1-13) to (1-17)

117 117 106 117 106 106 88,118 88 88 88

i.p., intraperitoneal.

to inhibit degranulation. These actions result in decreased hyperalgesia, plasma extravasation, and edema. At the level of the spinal cord, cannabinoid receptors are evident in the superficial laminae and a population of these receptors originate from the DRG. Cannabinoids interact with spinal CB, receptors to inhibit activation of capsaicin-sensitive fibers as well as to decrease activity of WDR neurons in response to noxious stimuli. These actions may result in the modulation of NMDA, adrenergic, and opioid receptor activity. Supraspinally, cannabinoids also decrease the responsiveness of nociceptive neurons and may modulate spinal cord neurons by descending control. The spinal and supraspinal actions result in antinociception as well as antihyperalgesia. Together, these results indicate that cannabinoid administration modulates hyperalgesia from different etiologies including inflammation and neuropathic pain. The latter is important because it suggests that cannabinoids might be effective in decreasing neuropathic pain, which, traditionally, has been difficult to treat. Furthermore, the results indicate that local administration of cannabinoids, particularly into peripheral sites, might be useful in producing analgesia while avoiding side effects.

TonicActivity at the Cannaninoid Receptor Although it is now well accepted that exogenously administered cannabinoids modulate nociceptive thresholds, only recently have the tools been available to evaluate whether endogenous cannabinoid activity contributes to nociceptive tone. This has been addressed using selective cannabinoid receptor antagonists (Table 4). As mentioned previously, inverse agonism has

8 been shown for the cannabinoid receptor antagonists, indicating that effects observed in the presence of the antagonist could be caused by either inhibition of endogenous cannabinoid activity, in which case the SR compounds would be acting as antagonists, or negative modulation of tonic receptor activity, in which case the SR compounds would be acting as inverse agonists. The presence of tonic cannabinoid activity caused by either endogenous cannabinoids or tonic receptor activity is important because it leads to the possibility that alterations in the cannabinoid system could affect basal nociceptive thresholds and be involved in the etiology of chronic pain. In support of this, endogenous levels of both anandamide and PEA in rat paw skin are 5-to IO-fold higher than levels in rat brain or plasma.47,gg The authors estimate that these levels are high enough to activate local receptors.47 Furthermore, either SR 141716A administered intrathecally to normal animals or a receptor knockdown of spinal CB, receptors produced thermal hyperalgesia. 64 The SR 14171 GA-induced hyperalgesia involved activation of the NMDA receptor because it could be blocked with either D-AP5 or MK-801. Because cannabinoids have been shown to presynaptically inhibit hippocampal glutamate release, these results might indicate that tonic activity of the cannabinoid receptor inhibits spinal glutamate release.85 Hypoactivity of this system would lead to increased spinal glutamate release, increased NMDA receptor activation, and hyperalgesia. In addition to tonic activity of spinal CB, receptors, CB, receptors in the RVM also show tonic activation as shown by ‘the SR 14171 GA-induced reduction of RVM “off” cell activity and enhancement of RVM “on” cell activity, suggesting that, under basal conditions, the cannabinoid system contributes to “off” cell activity and “on” cell inactivity.5g This modulation is independent of the opioid system because the effects of SR l41716A were unaffected by naloxone. As with the spinal cord, hypoactivity of the cannabinoid system in the RVM would lead to hyperalgesia. These studies suggest that activity at CB, receptors in the spinal cord and RVM contribute to nociceptive tone under normal conditions. It should be noted that some studies have found no modulation of basal nociceptive thresholds by the CB, receptor. Systemic administration of SR 141716A had no effect on either thermal or mechanical nociceptive thresholds in normal animals.45,100,101Additionally, CB, knockout mice do not show thermal or mechanical hyperalgesia, suggesting either that endogenous cannabinoid activity does not modulate normal nociceptive thresholds or that a compensatory mechanism is activated in the knockout mice.102,103 Further studies are necessary to evaluate the conditions

Cannabinoids

Modulate

Pain

in which regional cannabinoid receptors contribute to basal nociceptive thresholds. In addition to modulating basal nociceptive thresholds, some studies indicate that endogenous activity of both the CB, and CB, receptors acts to increase nociceptive thresholds during certain hyperalgesic states. This has been shown for the CB, receptor in the formalin and CCI models and for the CB, receptor in the formalin model.47,55,66 One interpretation of these results is that rather than tonic cannabinoid activity decreasing (and, thus, contributing to hyperalgesia), the cannabinoid system is acting as an endogenous analgesic system and is turned on in response to hyperalgesic conditions. Because cannabinoid receptor agonists will produce antihyperalgesia in both the formalin and CCI models, the endogenous receptor activity is not fully efficacious. If the source of the tonic activity is endogenous cannabinoids, drugs could be administered to prevent the uptake or metabolism of the cannabinoids or to otherwise potentiate their effects. Another interpretation of these results is that because the cannabinoid receptor is modulating nociceptive thresholds during hyperalgesia, changes in its activity could exacerbate or prolong the hyperalgesia. It should be noted that i.pl. SR 141716A was ineffective in modulating thermal nociceptive thresholds in the carrageenan model of inflammation.g6 Because endogenous cannabinoids have been measured in the uninflamed rat paw at concentrations that have been estimated to activate the receptor, this may represent a situation’in which a decrease in cannabinoid receptor activity corresponds to the development of hyperalgesia. Together, these studies show that there is tonic activity at the cannabinoid receptor during some hyperalgesic states. These results indicate that tonic activity of cannabinoid receptors modulates nociceptive thresholds under normal and hyperalgesic conditions. Spinal CB, receptors increase basal nociceptive thresholds potentially by decreasing spinal glutamate levels and subsequent NMDA receptor activation. CB, receptors in the RVM contribute to “off” cell activity and “on” cell inactivity, which might attenuate spinal nociceptive transmission. Based on endogenous cannabinoid levels in the paw skin, tonic activity of cannabinoid receptors in the paw might also modulate basal nociceptive thresholds. Furthermore, activity at cannabinoid receptors decreases nociception in some hyperalgesic states, specifically the formalin and CCI models. Together, these data indicate that endogenous activity at the cannabinoid receptor modulates basal nociceptive thresholds and attenuates nociception in certain states of hyperalgesia. Thus, changes in cannabinoid receptor activity

CRITICAL REVIEW/Richardson

9

could produce or prolong hyperalgesia and chronic pain. The tonic activity might be caused by either release of endogenous cannabinoids or tonic receptor activity. If endogenous cannabinoids are responsible, drugs that decrease the uptake, block the metabolism, or potentiate their effects may be useful as therapeutics.

Coadministration of Cannabinoids and p Opioids Because of the similarities in effects and receptor transduction mechanisms of cannabinoid and opioid receptor activation, much interest has surrounded possible interaction between the 2 systems. Before the identification of distinct cannabinoid receptors, it had been hypothesized that cannabinoids might even exert their effects through opioid receptors. Whereas there was evidence that Ag-THC could interact noncompetitively with u and A opioid receptors, cannabinoid structure-activity relationships in behavioral assays did not correspond well with IC,, values at the opioid receptors, suggesting that the cannabinoid effect was not mediated by a direct interaction with opioid receptors.lo4 However, an interaction between the systems was shown with cross-tolerance studies. Rats that were tolerant to morphine showed cross-tolerance to Ag-THC in the tail-flick assay. lo5 The converse was not true (ie, Ag-THC-tolerant animals did not display cross-tolerance to morphine-induced antinociception). One interpretation of these results is that u opioid activation is downstream of cannabinoid receptor activation and might mediate some of cannabinoid-induced antinociception. Recently, studies have been conducted evaluating the antinociceptive effects of coadministration of Ag-THC with u opioid receptor agonists (Table 5). Because none of the studies used isobolographic analysis to evaluate synergy, the term potentiation will be used to indicate a greater-than-additive effect of the combined drugs. Systemic administration of inactive doses of both compounds produced antinociception that could be blocked with a systemic administration of the CB, receptor antagonist SR 141716A, a systemic administration of the opioid antagonist naloxone, or intrathecal (i.t.) administration of the K opioid receptor antagonist norbinaltorphimine (nor-BNl).lo6 Similarly, i.t. administration of an inactive dose of Ag-THC potentiated antinociception produced by i.t. morphine, and

References 1. Nerlich Extensive mummy.

AG, Parsche pulmonary Virchows Arch

F, Wiest I, Schramel haemorrhage in 427:423-429, 1995

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this potentiation was sensitive to i.t. nor-BNl.88 Additionally, this could be blocked with antisera to dynorphin (I-B), dynorphin (l-13), and dynorphin (1-17).88 These results suggest that inactive doses of cannabinoids may release dynorphin into the spinal cord, resulting in the activation of K opioid receptors and potentiation of u opioid receptor activity. Consistent with this hypothesis, i.t. administration of dynorphin (1-B) and dynorphin (I-13) has been reported to enhance morphine antinociception.88,107 Furthermore, there is evidence that the metabolism of dynorphin to the receptor agonist leu-enkephalin also might enhance morphine antinociception.88 Together, these results suggest that coadministration of inactive doses of cannabinoids in combination with either active or inactive doses of u opioid receptor agonists can result in antinociception. If the same is true during hyperalgesia, it could provide a new treatment by which side effects of both cannabinoids and opioids are avoided without sacrificing the analgesic effects.

Conclusion The scientific understanding of the involvement of cannabinoids in nociception has greatly increased in the past few years because of the development of a number of technological tools, including the cloning of cannabinoid receptors, the discovery of endogenous cannabinoids, and the development of selective cannabinoid receptor antagonists. It now appears that cannabinoids are present in many regions involved in nocic’eptive processing, and that they are capable of modulating both basal and hyperalgesic nociceptive thresholds. Additionally, tonic activation of the cannabinoid system appears to contribute to nociceptive tone in both conditions. Furthermore, combining cannabinoids with other analgesics such as opioids might prove to be a mechanism by which analgesia can be produced in the absence of side effects. The recent advances in the cannabinoid field will facilitate further evaluation of cannabinoids in nociceptive processing. Continued scientific progress should help overcome the negative associations of cannabinoids present in our society and open the door for their clinical use as analgesics.

Acknowledgment The author thanks Ken Hargreaves comments and suggestions.

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