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Antinociception mechanisms of action of cannabinoid-based medicine: an overview for anesthesiologists and pain physicians
  1. Samer Narouze
  1. Center for Pain Medicine, Western Reserve Hospital, Cuyahoga Falls, Ohio, USA
  1. Correspondence to Dr Samer Narouze, Center for Pain Medicine, Summa Western Reserve Hospital, Cuyahoga Falls, OH 44223, USA; narouzs{at}


Cannabinoid-based medications possess unique multimodal analgesic mechanisms of action, modulating diverse pain targets. Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant derived) and synthetic cannabinoids (pharmaceutical). Cannabinoids exert an analgesic effect, peculiarly in hyperalgesia, neuropathic pain and inflammatory states. Endocannabinoids are released on demand from postsynaptic terminals and travels retrograde to stimulate cannabinoids receptors on presynaptic terminals, inhibiting the release of excitatory neurotransmitters. Cannabinoids (endogenous and phytocannabinoids) produce analgesia by interacting with cannabinoids receptors type 1 and 2 (CB1 and CB2), as well as putative non-CB1/CB2 receptors; G protein-coupled receptor 55, and transient receptor potential vanilloid type-1. Moreover, they modulate multiple peripheral, spinal and supraspinal nociception pathways. Cannabinoids-opioids cross-modulation and synergy contribute significantly to tolerance and antinociceptive effects of cannabinoids. This narrative review evaluates cannabinoids’ diverse mechanisms of action as it pertains to nociception modulation relevant to the practice of anesthesiologists and pain medicine physicians.

  • pain perception
  • pharmacology
  • chronic pain
  • education
  • analgesia

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Recently, our pain physicians survey revealed a mismatch between the pain physicians’ favorable attitude regarding the legitimacy of using medical cannabis for pain and their lack of knowledge and education.1

Traditionally, it was presumed that cannabinoids produce analgesia by activating specific cannabinoid receptors, particularly cannabinoids receptors type 1 (CB1) which is predominantly expressed centrally within the central nervous system (CNS), and CB2 which is predominately expressed within the immune cells peripherally. However, with recent advances in our knowledge, the interplay between cannabinoids and pain has become much more complex and multifaceted. It is well known now that cannabinoids act simultaneously or synergistically on multiple pain targets within the peripheral and CNS.2–4 Alongside acting on cannabinoid receptors, cannabinoids may modulate pain through interaction with the putative non-CB1/CB2 cannabinoid G protein-coupled receptor 55 (GPR55) and GPR18 which is also known as the N-arachidonoyl glycine receptor,5 6 as well as other well-known G protein-coupled receptors (GPCRs) such as serotonin (5-hydroxytryptamine, 5-HT) and opioids receptors.7 8

Moreover, cannabinoids can interact with different transient receptor potential ion channels subfamilies (transient receptor potential vanilloid (TRPV), TRPA and TRPM).3,4 The main function of TRPV1 is body temperature and nociception modulation. TRPV1 is involved with pain transmission and modulation, as well as the integration of diverse painful stimuli.9-11

Cannabinoids have various effects on the cys-loop ligand-gated ion channel superfamily (eg, nicotinic acetylcholine, glycine, glutamatergic and gamma aminobutyric acid (GABAA), GABAA-ρ, 5-HT3 receptors).12–20 Anandamide (AEA), Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) directly activate glycine receptors, contributing to cannabinoid-induced analgesia in inflammatory and neuropathic pain.13–16 While 2-arachidonoyl glycerol (2-AG) and CBD are positive allosteric modulators mainly at the α2-containing GABAA receptor subtypes.17 18 On the other hand, cannabinoids (THC) negatively allosterically modulate and inhibit nicotinic and 5-HT3 receptors.12 19 20

The anti-inflammatory action of cannabinoids may contribute to their analgesic effects.21 22 Cannabinoid (CBD) action as a CB2 inverse agonist may explain its anti-inflammatory properties.23

Some cannabinoids modulate and activate different isoforms of the nuclear receptor peroxisome proliferator-activated receptors (PPARα, β and γ). Endocannabinoids (AEA, 2-AG, noladin ether, virodhamine and oleamide), endocannabinoid-like compounds (oleoylethanolamide and palmitoylethanolamide (PEA)), and phytocannabinoids (THC, CBD) activate PPARα and PPARγ.24 Activation of all isoforms, but primarily PPARα and γ, contributes to the analgesic, anti-inflammatory, neuroprotective, neuronal function modulation effects of certain cannabinoids, alongside activation of CB1/CB2 receptors and TRPV1 ion channel.24

Interestingly, there is anatomical and biochemical evidence supporting the existence of functional link and reciprocal interactions between the endocannabinoid and opioid systems. The dopaminergic, glutamatergic, and GABAergic systems are key targets for this cross talk.25

Coincidentally, other non-cannabinoid constituents of the cannabis plant that belong to a diverse group of natural products (terpenoids and flavonoids) may add to the analgesic and anti-inflammatory effects of cannabis.26 Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant derived) and synthetic cannabinoids (pharmaceutical).


This narrative review is based on a systematic literature search (MEDLINE, PubMed and Ovid) to identify articles describing the antinociception mechanistic actions of cannabinoids with relevance to the clinical practice of pain medicine. When appropriate, articles’ references were searched manually to identify relevant important papers. The literature search was limited to articles published in English during the period from 1990 to 2020.

Endocannabinoids mechanism of action

AEA and 2-AG are the two key lipid neurotransmitters within the endocannabinoid system. They display slight differences in their mechanism of action. The differences noted here are important to overall action of the endocannabinoids in pain modulation.


AEA is a partial agonist at both CB1 and CB2 receptors, but a full agonist at the ion channel receptor transient receptor potential vanilloid 1 (TRPV1). AEA shows a selectivity for the CB1 receptor. Although AEA is a partial agonist, it has a higher affinity to the CB1 receptor than 2-AG.27 Once actions are carried out at the receptor, AEA is thought to possibly be taken up by transport proteins on both neurons and glia that mediate endocannabinoid uptake.28 AEA can play a dual role in nociception: antinociceptive at cannabinoid receptors and pronociceptive at the TRPV1 receptor.29 AEA has a noted ‘tetrad effect’ when injected into mice. The tetrad is a combination of inhibition of motor activity, catalepsy, hypothermia and hypoalgesia.30 AEA helps regulate pain, depression, appetite, memory and fertility. High areas of AEA synthesis take place in brain regions important to memory, higher thought processes and movement control.31

In addition, AEA has also been demonstrated to interact with other neurotransmitter systems that may play a role in nociception. Cannabinoids might directly inhibit 5-HT3 receptors, leading to analgesia, and neuroprotection effects.30 AEA exerts part of its CNS effects through the 5-HT3 receptors as well as the 5-HT1 and 5-HT2 receptors.30 32


2-AG is a full agonist at CB1 and CB2 receptors. 2-AG relays signals via a retrograde signaling cascade.8 When 2-AG is released, it controls the activity of the complementary pre-synaptic neuron by binding to the CB1 receptor.28 A variety of mechanisms have been suggested as to how 2-AG is induced to leave the postsynaptic cell. It is thought 2-AG may be secreted by simple diffusion, or the use of passive carrier proteins may be required to secrete 2-AG.28 Once bound to CB1, activation leads to impeding of neurotransmitter release in the presynaptic cell through the inhibition of voltage-activated calcium channels and enhancement of inwardly rectifying K+ channels in the cell.28 33

Subsequent to neuronal depolarization, the Ca2+-dependent release of glutamate from presynaptic vesicles activates NMDA receptors at the postsynaptic neurons leading to excitatory postsynaptic currents (EPSCs). This variation of membrane excitability quickly triggers the synthesis of 2-AG. Then, 2-AG travels retrograde to stimulate CB1 receptors on presynaptic terminals, which in turn activate K+ channels and inversely inhibit Ca2+ channels, thus inhibiting excitatory neurotransmitter release33 (figure 1). With 2-AG being present at higher levels in nervous tissue than AEA, 2-AG may have a greater role in analgesia and antinociception.

Figure 1

Synthesis of 2-AG and the retrograde signaling. (A) The variation of postsynaptic membrane excitability triggers the synthesis of 2-AG. (B) 2-AG travels retrograde to stimulate CB1 receptors on presynaptic terminals, which in turn activate K+ channels and inversely inhibit Ca2+ channels, thus inhibiting excitatory neurotransmitter release. 2-AG is metabolized in the presynaptic neuron with MAGL into arachidonic acid and glycerol. 2-AG, 2-arachidonoyl-glycerol; cAMP, cyclic adenosine monophosphate; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2, CNS, central nervous system; COX2, cyclooxygenase 2; DAGL-α and -β, diacylglycerol lipase-α or -β; MAGL, monoacylglycerol lipase; PLCβ, phospholipase Cβ; PLD, phospholipase D; PIP2, sn-2-arachidonoyl- phosphatidylinositol-4,5-bisphosphate. (illustrated by Samer Narouze, MD, PHD, and used with permission).

Endocannabinoids and pain modulation

Endocannabinoids regulate various cerebral functions including nociception, mood, appetite, and memory. They are sensitized on demand, when noxious stimuli occur, there is an increase in endocannabinoid release, thus leading to pain modulation effects.31 Animal studies show endocannabinoids to have analgesic actions in the periphery, spinal and supraspinal pain pathways31 (table 1).

Table 1

Cannabinoids multimodal analgesic mechanisms of action

Peripheral mechanisms

The cannabinoid receptors in the periphery play a vital role in analgesia. Antinociceptive effects are noticed when AEA and 2-AG are administered locally and systemically. Models of inflammatory pain show elevated concentrations of AEA and 2-AG in peripheral tissues.29 CB2 receptors are also present in the periphery leading to 2-AG mainly regulating actions at these receptors. 2-AG has been studied to show multiple mechanisms leading to pain modulation which include inhibiting production and release of reactive oxygen species and cytokines, and in addition 2-AG will release peripheral endogenous opioids.29 There is more research describing the anti-inflammatory and antinociceptive mediated actions of 2-AG compared with AEA. There are also CB1 receptors in the periphery that localize on sensory afferent terminals where endocannabinoids act to gate the transduction of pain from noxious stimuli.29

Spinal mechanisms

A vital region for pain processing occurs at the dorsal horn in the spinal cord. Endocannabinoids are shown to have antinociceptive effects at this region and phase of the pain-signaling pathway due to high expression of CB1 receptors. At this level, 2-AG inhibits the release of pronociceptive neurotransmitters from primary afferent terminals mediated by CB1 receptors.29 In contrast, AEA was shown to have effects on acute and chronic pain via mediation of CB2 receptors expressed on inhibitory interneurons and glial cells.29 To get a better picture for when each of the endocannabinoids takes effect, a surgical incision model was used to assess spinal levels of endocannabinoids. Hours after a peripheral surgical incision, there was a marked decrease in AEA concentrations, whereas no changes in 2-AG concentration was observed.29 AEA concentrations returned to baseline as nociceptive behavior subsides. 2-AG concentrations increased at a later time point in conjunction with glial cell activation, CB2 receptor upregulation, and resolution of the pain state.29

This research shows the difference in the timing of endocannabinoid actions of pain modulation. AEA exerts its actions at the onset of pain, whereas 2-AG plays a role in the resolution of pain.

Supraspinal mechanisms

Endocannabinoids modulate ascending pain signals in the thalamus, descending signals in the brain stem, and pain sensation in the frontal-limbic circuits.29 AEA has a biphasic effect on the supraspinal level of pain modulation. AEA is released due to stimulation of the periaqueductal gray (PAG) or peripheral inflammatory insult.27 In acute pain, AEA that is released causes antinociceptive actions. When high concentrations of AEA occur due to prolonged stimulation, AEA modulates pronociceptive responses via TRPV1 binding.28

AEA and 2-AG synergistic effect

AEA and 2-AG have a synergistic yet differential role regarding pain signaling at the spinal and supraspinal levels. Stress-induced analgesia exhibits a synergistic effect of AEA and 2-AG modulation. Signaling at the PAG can result in induction of descending inhibitory GABAergic signaling to the spinal cord, thus mediating stress-induced analgesia.28 In a prolonged foot shock modulation study, both endocannabinoids were found to be released in the ipsilateral lumbar V dorsal root ganglion on stimulation.34 The CB1 receptors at the dorsal root ganglion and CB2 receptors at the periphery involve a synergistic interplay between AEA and 2-AG.34 The signaling mechanism is strengthened when the molecular pathway switches. Both endocannabinoids levels were enhanced after 3 and 7 days of chronic constriction injury at the sciatic nerve of a rat.34 After the 3-day mark, endocannabinoid levels were increased only at the spinal cord and PAG. However, after 7 days, elevated concentrations were detected in the rostral ventral medulla as well.34 This study provides evidence of endocannabinoid cooperation regarding synergistic involvement in the regulation of pain. This combined effort is present at both the spinal and supraspinal levels and can modulate chronic pain states.

Chronic pain enhances the endocannabinoid signaling effects of both AEA and 2-AG. An upregulation of CB2 receptors found in such pain states would benefit from endocannabinoid agonism.28 2-AG signaling cascades from microglial cells mediate effects in persistent pain.28 Although CB2 receptors are widely studied in the literature for chronic pain, CB1 receptors were also shown to provide antinociceptive benefit when agonists are present. The spinal level endocannabinoids have the greatest modulation of pain in chronic pain states displaying a synergistic benefit of the endocannabinoid agonists.

Endocannabinoids receptors

CB1 receptors

Central CB1 receptors

CB1 receptor is thought to be the most abundant GPCR in the mammalian brain, thus it is referred to as the ‘brain cannabinoid receptor’.35 CB1 receptors are expressed centrally in all brain structures, and in decreasing density from the olfactory bulb, cerebellum, hippocampus, basal ganglia, cortex and amygdala, to the hypothalamus, thalamus and brainstem.36

They are expressed in most brain areas on presynaptic terminals of both GABAergic neurons.37 Moreover, CB1 receptors can also be expressed post-synaptically where it can form heterodimers in association with other GPCRs including the dopamine D2, adenosine A2 or orexin type-1 receptors38–40 (table 2).

Table 2

Cannabinoids mechanism of action in chronic pain

The intracellular region of CB1 is most regularly coupled to Gi/o proteins. Consequently, the activation of CB1 receptors inhibits adenylate cyclase activity with subsequent reduction of intracellular cyclic adenosine monophosphate (cAMP) level or promotes mitogen-activated protein kinase (MAPK) activity35 (figure 2). Decreased cAMP level leads to activation of voltage-gated K+ and inhibition of Ca2+ channels, thus inhibiting neurotransmitters release.41–43 In neurons, CB1 activation of Gi/o can also directly inhibit voltage-activated Ca2+ channels0.33

Figure 2

CB1 receptor activation. The intracellular region of CB1 is most regularly coupled to Gi/o proteins. the activation of CB1 receptors by binding to a ligand 2-arachidonoyl-glycerol (2-AG) inhibits adenylate cyclase activity with subsequent reduction of intracellular cyclic adenosine monophosphate (cAMP) level or enhances MAPK activity. Decreased cAMP level leads to activation of voltage-gated K+ and inhibition of Ca2+ channels, thus inhibiting neurotransmitters release (illustrated by Samer Narouze, MD, PHD, and used with permission). CB1, cannabinoids receptors type 1; GPCR, G protein coupled receptor.

Neuronal depolarization rapidly triggers the synthesis of endocannabinoids, particularly 2-AG, at postsynaptic neurons. Subsequently, 2-AG travel backwards to stimulate CB1 receptors on presynaptic terminals, then after it is inactivated by hydrolytic enzymes. This ‘on demand’ synthesis of endocannabinoids leads to CB1-mediated activation of K+and inhibition of Ca2+ channels thus controlling both excitatory and inhibitory neurotransmitter release, which eventually tunes the duration of synaptic activity and synaptic plasticity.44 45

CB1 is also found in non-neuronal cells of the brain, predominately in astrocytes, where its activation stimulates the release of neurotransmitters. Unexpectedly, astroglial CB1 receptors activation seems to induce intracellular Ca2+ levels, triggering the release of glutamate and the subsequent activation of presynaptic metabotropic glutamate receptors.46–49

Peripheral CB1 receptors

CB1 receptors are also expressed in the peripheral nervous system and in almost all mammal tissues and organs including adrenal glands, smooth and skeletal muscle, heart, lung, gastrointestinal tract, liver, male and female reproductive systems, bone, adipose tissue and skin.33 The CB1 receptors play a vital role in the maintenance of homeostasis and regulating adrenal, cardiovascular, lung, gastrointestinal and reproduction functions, among others.

Peripheral CB1 receptors are mainly localized on sensory afferent terminals where endocannabinoids act to gate the transduction of pain from noxious stimuli.4 Thus playing an important role in peripheral pain sensitization.

Central CB2 receptors

The role of CB2 in the brain is still controversial. In contrast to CB1, CB2 receptors in the brain are limited, and its expression is restricted to specific neuronal cells and becomes abundant in activated microglia and astrocytes.46 49

Like CB1, CB2 receptor is a GPCR and is coupled to Gi/Go α proteins. Thus, its stimulation inhibits adenylate cyclase activity and activates MAPK.33

Peripheral CB2 receptors

In contrast, CB2 receptors are abundantly expressed in the immune system cells such as monocytes, macrophages, B-cells and T-cells, and mast cells. CB2 receptor activation reduces the release of pro-inflammatory cytokines and lymphoangiogenic factors.50–53 Moreover, CB2 receptors are also present in other peripheral organs playing a role in the immune response, including the spleen, tonsils, thymus gland and keratinocytes, as well as in the gastrointestinal system.33

Accordingly, CB2 receptors represent key regulators of inflammatory and nociceptive responses and can control the activation and migration of immune cells.54 55

Other putative endocannabinoid receptors: TRPV1 and GPR55

Transient receptor potential vanilloid 1

The TRPV1 channel, also known as the capsaicin receptor or vanilloid receptor 1, was the first member of the TRPV channel subfamily to be discovered and cloned.56 It is characterized by weak voltage sensitivity and a non-selective permeability to monovalent and divalent cations including Mg2+, Ca2+ and Na+.

TRPV1 channels are activated by capsaicin, endocannabinoids (AEA, PEA, N-oleyl-dopamine, N-arachidonoyl dopamine), and phytocannabinoids (CBD, CBN, CBG, CBC, THCV, CBDV).57–59

TRPV1 function is heavily dependent on the binding of key regulatory proteins that induce changes in its phosphorylation state. The phosphorylation induced by ATP, protein kinase A, PKC, phosphoinositide-binding protein and phosphatidylinositol 4,5-bisphosphate (PIP2), is required for TRPV1 activation and cation gating. TRPV1 activation contributes to pain transmission, neurogenic inflammation, synaptic plasticity, neuronal overexcitability and neurotoxicity.59–65

TRPV1 ‘desensitization’ occurs as the rise of intracellular Ca2+ following TRPV1 stimulation activates proteins (ie, calmodulin) that stabilize the channel in a closed conformational state, or Ca2+-dependent phosphatases, (ie, calcineurin) which dephosphorylate and inactivate TRPV1. 60–64 This fast process of TRPV1 desensitization and inactivation is thought to underlie the paradoxical analgesic, anti-inflammatory and anti-convulsant effects of TRPV1 agonists.59 66 67

TRPV1 channels are largely expressed in dorsal root ganglia, and sensory nerve fibers (Aδ and C-type).68 In sensory neurons, TRPV1 channels work as molecular integrators for multiple types of sensory inputs that contribute to generate and transmit pain. In central neurons, lower amounts of TRPV1 channels are expressed both presynaptically and postsynaptically, where they act to regulate synaptic strength.69 70 They usually affect pain, anxiety and depression by inducing effects opposite to those exerted by CB1 receptors in the same context.33

Moreover, there is intracellular crosstalk between TRPV1 and CB1 or CB2 as they are colocalized in peripheral and central neurons (sensory neurons, dorsal root ganglia, spinal cord, brain neurons).70 71 Recently, a multiplicity of interactions between cannabinoid, opioid and TRPV1 receptors in pain modulation was discovered.72 This provides a great opportunity for the development of new multiple target ligands for pain control with improved efficacy and side effects profile. The interaction between the endocannabinoid system and TRPV1 receptors highlights the rationale for using very hot water (>41°C) and topical capsaicin cream in the management of acute cannabinoid hyperemesis syndrome.73


GPR55 also belongs to the large family of GPCRs and is currently considered a potential cannabinoid receptor. Some consider it to be the CB3 receptor. The endogenous ligand of this receptor is lysophosphatidylinositol.74 75

GPR55 is activated by Δ9-THC while antagonized by CBD. Conflicting data exist regarding the likelihood that low concentrations of endocannabinoids (AEA, 2-AG, virodhamine, noladin ether and PEA) may activate GPR55.76 77 These controversies might be explained by biased signaling depending on the cell type and condition, or the formation of heteromers between GPR55 and CB1 receptors.78 79

The exact function of GPR55 is not fully understood. However, that activation of GPR55 might play an opposite role to CB1 by enhancing neurotransmitter release.33 GPR55 also involved in mechanical hyperalgesia resulted from neuropathic and inflammatory pain.5

Phytocannabinoids (THC and CBD)


THC is an analog to the endocannabinoid, AEA. THC determines most of the pharmacological effects of cannabis. This includes its psychoactive, memory, analgesic, anti-inflammatory, antioxidant, antipruritic, bronchodilator, antispasmodic and muscle-relaxant activities.80 81 THC acts as a partial agonist at CB1 and CB2 receptors.23 THC has a very high binding affinity to CB1 receptor which mediates its psychoactive properties. Interestingly, most of the negative effects of THC such as psychogenic effects, impaired memory, anxiety, and immunosuppression can be reversed by other ingredients of the cannabis plant (other cannabinoids, CBD, terpenoids and flavonoids).81 82


CBD, is the other important cannabinoid in the cannabis plant. It is the minimally psychoactive analog of THC. CBD have significant analgesic, anti-inflammatory, anticonvulsant and anxiolytic activities without the psychoactive effect of THC.83 CBD has weak binding affinity for either CB1 or CB2 receptors. However, in the presence of THC, CBD can antagonize CB1 and CB2.84 Moreover, CBD may act as a non-competitive negative allosteric modulator of the CB1 receptor, thus reducing the effects of THC and AEA.85 This may explain the ‘entourage effect’ that CBD displays, as it improves the tolerability and safety of THC by reducing the likelihood of psychoactive effects and other adverse effects such as tachycardia, sedation, and anxiety.81 86

Mechanisms of action in pain modulation

The phytocannabinoids THC and CBD, are lipophilic substances that readily cross the blood brain barrier and interact with receptors in both the central and peripheral nervous system.87

Cannabinoids exert an analgesic effect, especially in hyperalgesia and inflammatory states88 (table 3).

Table 3

THC and CBD mechanisms of action in pain modulation


THC exhibits CB1 receptor-mediated antinociception through activation of supraspinal sjoites and descending serotonergic and noradrenergic pain modulatory pathways to produce antinociceptive effects via spinal 5-HT7, 5-HT2A and alpha-2 adrenoceptors activation.89 90

The frontal-limbic distribution of cannabinoid receptors explains the central mechanism of THC analgesia as it targets preferentially the affective qualities of pain. Functional MRI revealed that amygdala activity contributes to the dissociative effect of THC on pain perception related to cutaneous ongoing pain and hyperalgesia that were temporarily induced by capsaicin.91 THC decreased the reported unpleasantness associated with pain, but not the hyperalgesia nor the intensity of ongoing pain . In addition, THC lowered functional connectivity between the amygdala and primary sensorimotor areas in the setting of persistent pain. The authors concluded that peripheral mechanisms alone cannot account for the dissociative effects of THC on the pain that was observed, and amygdala activity contributes to inter-individual response to cannabinoid analgesia.91

The analgesics effects of THC are mediated through mechanisms distinct from those responsible for the psychoactive effects. In mice, THC was shown to have additive analgesic effect with kappa opioid receptor agonists. This antinociception effect was blocked by the kappa antagonist, norbinaltorphimine. While the more selective mu receptor antagonist, naloxone, failed to block the antinociceptive effect. In contrast, opioid receptor antagonism does not reverse the psychoactive effects of THC.92

Cannabinoids may exert other non CB1/CB2 receptor-mediated antinociceptive effects by inhibiting nicotinic, 5-HT3 and N-methyl-d-aspartate receptors.3 92

CB2 receptors serve an important role in immune function, inflammation, and pain modulation specially in allodynia and hyperalgesia states.93 94 The presence of CB2 receptors on microglia within the nervous system may explain the cannabinoids role in neuropathic pain modulation by reducing cytokine-mediated neuroinflammation.93 94

CB2 receptor expression has been demonstrated in areas of the peripheral and CNS relevant to pain perception and modulation, including the dorsal root ganglion, spinal cord and microglia. This explains the analgesic effects produced by CB2 agonists.95–99

CB2-selective agonists suppress neuronal activity in the dorsal horn via reduction in C-fiber activity and wind-up involving wide dynamic range neurons.100 101 There is increase in peripheral CB2 receptor protein or mRNA in inflamed tissues. It is also increased in the dorsal root ganglion in neuropathic conditions.102–104 As such, cannabinoids possess unique, multimodal analgesic mechanisms of action.


CBD regulates the perception of pain mainly through non CB1/CB2 mechanisms. CBD interacts with a significant number of other targets, including non-cannabinoid GPCRs (eg, 5-HT1A), ion channels (TRPV1, TRPA1, TPRM8, GlyR), PPARs. Moreover, CBD augments AEA effects by inhibiting its uptake as well as its metabolizing enzyme, ‘the fatty acid amide hydrolase’.4 5 105

CBD can act synergistically with THC and contribute to its the analgesic effect while providing an ‘entourage effect’, minimizing the negative psychoactive effects of THC.81 The depends on the differences in concentration of THC/CBD in the cannabis chemovar. Although CBD as a monotherapy has not been evaluated clinically in the management of pain, its anti-inflammatory, antispasmodic effects and good safety profile suggest that it could be a safe and effective analgesic.106 107

Cannabinoids opioids cross-modulation


There is good anatomical and biochemical evidence supporting the existence of reciprocal interactions between the cannabinoids and opioids systems related to several pharmacological actions; mainly with antinociception, tolerance, dependence and reward. However, antinociception, cross-tolerance and cross-sensitization may not always be bidirectional and may be asymmetric.25

Both cannabinoid and opioid receptors are expressed mainly on presynaptic terminals and they both belong to the rhodopsin subfamily of G-protein-coupled receptor (GPCR) superfamily that couple to Gi/Go GTP-binding proteins.108 Hence, activation of both receptors initiates similar downstream signaling leading to inhibition of neurotransmitters release. This occurs through inhibition of adenylyl cyclase activity and reduction in cAMP level. Decreased cAMP level leads to activation of voltage-gated K+and inhibition of Ca2+ channels, thus inhibiting neurotransmitters release.41–43 109

CB1 cannabinoid receptor and mu opioid receptor are spread across the CNS (limbic system, brain stem and spinal cord) in an overlapping pattern. Both receptors colocalize on the ventral and dorsal striatum (basal ganglion) GABAergic neurons.110–112 This implies coupling to similar second messenger transmitters, suggesting the formation of heterodimers between cannabinoids and opioids receptors.113 This established functional link explains the similar antinociception actions induced by both opioid and cannabinoid receptors agonists.114

There are synergistic interactions between cannabinoids and opioids analgesic effects.108 Cannabinoids induces antinociceptive effects through other distinctive mechanisms than those responsible for the psychoactive effects. THC has cumulative analgesic effects with kappa opioid receptor agonists. kappa antagonists can block this effect, however, opioid receptor antagonists do not reverse the psychoactive effects of THC.92 When THC and morphine are coadministered, only 25% of the morphine dose was required to produce significant pain reduction.115 Surprisingly, THC (1–10 µM) may displace opiates from the μ-opioid receptor, and negatively allosterically modulate the μ- and δ-opioid receptors.92 Moreover, CB2 receptor agonists can produce peripheral analgesia by eliciting the release of the endogenous opioid beta-endorphin.3 116

The reciprocal interactions between cannabinoids and opioids may provide an opportunity for therapeutic synergy. In difficult-to-treat pain circumstances, a complimentary treatment with small dose of cannabinoid receptor agonists and opioid may be desirable to avoid the unfavorable side effects of opioids and the dose-limiting negative psychotropic effects of cannabinoids while attaining better analgesic effects than with either agent alone.116–118

Tolerance to antinociception

When it comes to the development of tolerance to the antinociceptive effects, the interactions between cannabinoids and opioids are complex, asymmetric and not necessarily bidirectional or reciprocal. In mice, morphine pretreatment induced tolerance to the acute antinociceptive effects of THC.119 On the other hand, morphine tolerant rats exhibited sensitization to the acute antinociceptive effects THC.120

Chronic administration of selective kappa opioid receptor agonists produced tolerance to the antinociceptive effects of intrathecal THC,121 indicating that downregulation of kappa receptors contributes to the development of tolerance to THC antinociception.122 Likewise, chronic exposure to exogenous cannabinoids (THC) led to cross-tolerance to morphine’s acute antinociceptive effects, and kappa receptor agonists.119 123 However, endogenous cannabinoids (AEA) tolerant mice did not exhibit cross-tolerance to the antinociception induced by mu, delta or kappa agonists.124

The interplay between chronic exposure to opioids or cannabinoids and the density of the reciprocal receptors is rather complex and dynamic. Chronic morphine exposure can lead to decrease,125 increase126 or no change119 in CB1 receptor density.

However, chronic administration of intrathecal morphine boosted the expression of spinal CB1 and CB2 receptors.127 This may rationalize the sensitization to the acute antinociceptive effects of the synthetic THC analog (CP 55, 490) that is observed in morphine-tolerant animals.125

Conversely, cannabinoid tolerance was associated with a modest increase in mu receptor density in the limbic system, PAG, and thalamus.125 The increase in mu receptor conflicts with the displayed cross-tolerance to the acute antinociceptive effect of morphine with chronic exposure to cannabinoids.119 125

Calcitonin gene-related peptide (CGRP) is an important modulator of opioid induced tolerance at the spinal level.128 Chronic morphine exposure leads to increased CGRP expression in the dorsal horn of the spinal cord contributing to the development of tolerance to morphine antinociceptive effects.128 129 Selective CB1 cannabinoid inverse agonist (AM 251) can diminish the over-activity of CGRP and impede acquiring tolerance to the antinociceptive effects of morphine.130

In conclusion, there is a fast-growing interest among the public and healthcare professionals in using cannabinoid-based medicine in treating chronic pain to help curbing the opioid epidemic. While there is a sound basic science literature about the analgesic effects of cannabinoids and opioids-cannabinoids reciprocal interactions and crosstalk, there is a paucity of translational research.

The categorization of marijuana (cannabis, THC) by the United States Drug Enforcement Agency adds a barrier to conducting high-quality rigorous trials following Food and Drug Administration (FDA) standards for safety and efficacy. Public advocacy and politics have surpassed and outpaced quality clinical evidence. The challenges and limitations of the current clinical research stem from flawed methodology, high risk of bias, small size, recruiting previous cannabis users, difficulties with blinding, variable doses and rout of administrations, inconsistency in dose–response evaluations and lack of long-term health outcomes. However, the lack of evidence for cannabinoid-based medicine efficacy does not necessarily equate with evidence of a lack of efficacy. Future research may also focus on modulating endocannabinoids levels by pursuing novel molecules that would slow down the uptake and breakdown of endocannabinoids.



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  • Contributors This is an original work and was not submitted to any other journals.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.