1. Role of CB2 Receptors In Pain and Inflammation
Nandita Pandey
M.S. (Pharm) Pharmacology & Toxicology

2. ENDOCANNABINOID SYSTEM
• The Endocannabinoid System is a biological
system involving the endogenous lipid-based
retrograde neurotransmitters which bind to
the cannabinoid receptors, as well as the
cannabinoid receptor proteins which are in the
CNS and PNS.
• The endocannabinoid system is defined as the
ensemble of the two 7-TM domain GPCR:
CB1R, CB2R and GPR55 (Novel CR, osteoblast
and osteoclast, regulate bone function) for
Δ(9)-tetrahydrocannabinol.
• Anandamide and 2-AG are the endogenous
ligands.
• CB1R: Adverse neurological effects such as
depression, suicidal ideation and anxiety and
hence, limited therapeutic use
Bihua Bie,et al, Current Opinion, 2018

3. LOCATION AND Function OF CB2 RECEPRTORS
 Peripheral: Circulating immune cells, the spleen and on macrophage
derived cells including osteocytes, osteoclasts and hepatic Kupffer
cells; mediates anti-nociceptive and anti-inflammatory effects.
 CB2R are chiefly expressed in neuronal Somatodendritic areas
(postsynaptic)and glial cells, brainstem and the hippocampal CA2/3
pyramidal neurons
 CB2R is highly inducible under some pathological conditions (e.g.,
addiction, inflammation, anxiety, etc.), CB2R expression is enhanced in
the brain.
 CB2Rs appear to be an important substrate for neuroprotection. The
cannabinoid type 2 (CB2) receptor is primarily expressed on glial cells
only when there is active inflammation and appears to be devoid of
undesired psychotropic effects or addiction liability
 Anandamide has low intrinsic activity but enhanced during
pathological conditions and 2-AG acts as a full agonist.
Yuchao Shang & Yuying Tang (2016),
Impact of cannabinoid type 2 receptors in neuroprotection Q Xin et al

4. CB2R MECHANISM OF ACTION
DOI:10.1124/mol.114.094649
Stimulate glucose
consumption via the
ERK cascade also
regulates apoptosis.

5. The CB1 cannabinoid receptor is coupled to ceramide generation. Activation of the CB1 receptor can produce
two peaks of ceramide. Short-term ceramide generation involves sphingomyelin (SM) hydrolysis via
sphingomyelinase (SMase) activation possibly through the adaptor protein FAN. Long-term ceramide
generation may occur via serine palmitoyltransferase (SPT) induction and enhanced ceramide synthesis de
novo. The two pools of ceramide elicit biological responses (e.g. metabolic regulation and apoptosis) through
regulation of various targets, for example the Raf-1/MEK/ERK cascade.
G. Velsasco et al, Life Sciences 77, 2005

6. CB2 RECEPTORS and microglia
Yutaka Nakagawa, pharmaceuticals, 2014
 Microglial activation occurs in response to diverse CNS
insults, and as a result, a transition is seen in
microglial phenotype from anti-inflammatory to the
reactive (proinflammatory) phenotype.
 CB2R mainly expressed in microglia, inhibit microglia-
mediated neurotoxicity by pro-inflammatory
molecules and by modulating macrophage migration
in several pathological conditions.
 CB2 activity facilitates the transformation of microglial
cells from the M1 to M2 phenotype which is
suggested to favor phagocytosis and reparative
mechanisms
 Reactive microglia express CB2 mRNA in the spinal
cord under neuropathic pain conditions such as
peripheral nerve injury, chemotherapy- induced pain.
 Reduction of basal Nerve Growth Factor (NGF) tone,
induction of beta-endorphin release from
keratinocytes, and direct action on nociceptors.
Resolvin D1: Involvement in promoting restoration of normal cellular function
following the inflammation that occurs after tissue injury.; anti-inflammatory.
Lipoxin A4 is a dual acting mediator and activates specific cellular pathways to
elicit both anti-inflammatory and pro-resolution effects

7. CB2 RECEPTORS IN ALZEHIMER’S DISEASE
Ester Aso and Isidro ferrer, frontiers in neuroscience, 2016
Front. Neurosci., 02 February 2017
Sec. Neurodegeneration

8. CB2 RECEPTORS in depression
Michelle Roche, David P Finn, mdpi journal pharmaceuticals, 2010
 Transgenic mice engineered to over-express the CB2 receptor
exhibited reduced depressive-like behaviour in the tail
suspension test and in a novelty suppressed feeding test,
compared with wildtype controls.
 Stimulation of CB2 receptors, either by endocannabinoids or
exogenously administered CB2 receptor agonists, may reduce
neuroinflammatory responses, enhance neurogenesis and alter
levels of neurotransmitters and neuropeptides.
 Most importantly, pre-administration of the CB2 receptor
antagonist AM630, fully abrogated the anxiolytic and the anti-
depressant effects of BCP.
 Taken together, these preclinical results suggest that CB2
receptors may provide alternative therapeutic targets for the
treatment of anxiety and depression.

9. CB2 RECEPTORS IN PAIN MODULATION
The endocannabinoid system and neuropathic pain, Rafael Maldonado et al, NeuPSIG, 2015
Yuchao Shang & Yuying Tang (2016): The central cannabinoid receptor type-2 (CB2) and chronic pain,
International Journal of Neuroscience.
Release of anti-inflammatory mediators, including macrophages, IL-10, INF-y
and IL-12.
Activation of CB2 may suppress the production of proinflammatory cytokines,
thus inhibiting the neuronal activity, normalizing nociceptive thresholds and
producing antinociception in inflammatory pain states.
The systemic administration of AM1241 or JWH133 significantly suppressed
the expression of Fos protein, a marker of neuronal activity in the superficial
and neck region of the dorsal horn, and attenuated the firing activity of spinal
wide dynamic range (WDR) neurons in rats receiving intraplantar carrageenan
Combination of immunosuppression + anti-inflammatory factor leads to
decrease in chronic pain states.

10. CB2 IN VARIOUS PAIN CONDITIONS
Yuchao Shang & Yuying Tang (2016): The central cannabinoid receptor type-2 (CB2)
and chronic pain, International Journal of Neuroscience.
Fibroblast like synoviocytes are expressed in RA which expresses the CB1 and CB2
receptors.
Activation of FLS depress the pain stimulus in chronic pain states.
Regulation of GABA and Glutamate release.
Glycine receptors also play a significant role as potentiation of these receptors
showed analgesic properties in mice.
Intrathecal administration of nonselective CB1/CB2 agonist CP55, 940 increases
tail flick latency, and inhibits tactile allodynia in the rats with chronic L5-6 spinal
nerve ligation.
Intrathecal administration of WIN 55, 212-2, a nonselective CB1 and CB2 agonist
significantly alleviated the mechanical allodynia, peripheral and spinal CB2
receptor-mediated anti-hyperalgesic effect in this rodent model of cancer pain.
Systemic administration of non-selective CB1 and CB2
agonist WIN 55,212-2 significantly reduced the
thermal hyperalgesia and mechanical allodynia
evoked by paclitaxel in the rats.
CB2 receptor agonists such as MDA19 or MDA7 can
also significantly attenuate mechanical allodynia
induced by paclitaxel in a dose-related manner
administered systemically in rodents.

11. ANIMAL MODELS OF CB2 RECEPTOR PAIN MODULATION
The endocannabinoid system and neuropathic pain, Rafael Maldonado et al, NeuPSIG, 2015

12. ANIMAL MODELS OF CB2 RECEPTOR PAIN MODULATION
The endocannabinoid system and neuropathic pain, Rafael Maldonado et al, NeuPSIG, 2015

13. Analgesic Effect of CB2 Selective Agonists in Pre-Clinical Pain Models
Mini-Reviews in Medicinal Chemistry, 2009, Vol. 9, No. 1

15. THANK YOU!