Table 2.

Effects of selected cannabinoids on the regulation of pain and inflammation in arthritis models in vivo and in vitro

Compound	Model	Key findings	References
JWH-133	CIA mouse model	↓ TNFα, IL-1β, IL-6, synovial hyperplasia, cartilage damage, bone destruction, M1-like macrophages, osteoclast formation, osteoclastic bone resorption, RANKL-induced NF-kB activation in the osteoclast precursors ↑ IL-10	[135]
	MIA-induced OA rat model	Systemic administration: ↓ pain, inflammation, spinal astrogliosis, MMP-2, MMP-9 activity Spinal administration: ↓ noxious-evoked responses of spinal neurons	[98]
	TNFα-stimulated; RA/OA FLS and CIA mouse model	In vivo: ↓ IL-6, MMP-3, CCL2 In vitro: ↓ arthritis score, inflammatory cell infiltration, bone destruction and anti-CII IgG1 production	[136]
	IL-1β-stimulated human RA FLS	JWH-133 pretreatment: no reduction of IL-1β-induced IL-6 and IL-8 production, ↑ COX-2	[110]
JWH-133 or ACEA	CB1KO, CB2KO and WT mice with MIA-induced OA	CB1KO mice: ↑ arthritis affective manifestations JWH-133: ↓ nociceptive and affective OA alterations ACEA: ↓ nociceptive and affective OA alterations, ↑ memory	[117]
JWH-133 or JWH-015	Kaolin/carrageenan-induced or Freund’s adjuvant arthritis rat models	JWH-133 and JWH-015 in control animals: ↑ synovial blood flow (JWH-133’s effect blocked by AM630 or SB366791) Arthritic animals: ↓ of vasodilatory effect of JWH-133	[137]
JWH-015	IL-1β-stimulated RA FLS and rat adjuvant-induced arthritis model	In vitro: ↓ IL-6, IL-8, COX-2, phosphorylation of TAK1 and JNK/SAPK (still effective after CB2 knockdown) In vivo: ↓ arthritis, pain, bone destruction, RANKL level; ↑ OPG level	[129]
JWH-133 or HU-308 (in vitro only) or AM630	Osteoblast-bone marrow co-cultures and RANKL- and M-CSF-generated osteoclasts; CB2KO and WT mice	In vitro: JWH-133 and HU-308: ↑ osteoclast formation AM630: ↓ osteoclast formation and activity In vivo: AM630: protected against bone loss in WT, but not CB2-/- mice	[138]
HU-308	IL-1β-, TNFα- or LPS-stimulated FLS from OA or RA patients	↓ FLS proliferation, MMP-3, MMP-13, IL-6 production, IL-1β-induced activation of extracellular ERK 1/2 and p38 MAPK	[141]
	CIA mouse model; LPS-stimulated mouse peritoneal macrophages from WT or CB2KO mice	In vivo: no inhibition of incidence of the development of CIA, ↓ severity of CIA, joint swelling, synovial inflammation, joint destruction, serum levels of anti-collagen II antibodies In vitro: ↓ IL-6, TNFα (no effect on macrophages from CB2KO mice)	[132]
	Surgically-induced or spontaneous OA in CB2KO or WT mice	More severe OA in CB2KO mice HU-308: ↓ severity of OA	[109]
WIN55,212-2	TNFα-stimulated FLS from OA and RA patients	Low concentrations: ↓ IL-6, IL-8, MMP-3 production (effect independent on CB1 or CB2 activation, but attenuated by TRPV1 or TRPA1 inhibition); ↑ FLS adhesion High concentrations: ↓ IL-6, IL-8; ↑ extracellular MMP-3 (effect decreased by BAPTA, metformin, A967079 and COR170); ↓ FLS adhesion and proliferation	[133]
	IL-1β-stimulated human OA chondrocytes	↓ ADAMTS-4 activity (effect abolished by JTE907, but not MJ15) ↓ expression of syndecan-1 (overexpression of syndecan-1 reversed the inhibitory effect of WIN-55 on the ADAMTS-4 activity)	[142]
	IL-1β-stimulated human OA chondrocytes	↓ MMP-3, MMP-13, TIMP-1, TIMP-2 gene expression ↓ MMP-3, MMP-13 protein production	[143]
	IL-1α-stimulated bovine articular chondrocytes and cartilage explants	↓ NO production in chondrocytes (effect potentiated by AM281 and AM630) ↓ release of sulphated glycosaminoglycans in cartilage explants	[120]
WIN55,212-2 or HU-210	IL-1α-stimulated bovine chondrocytes and explants	WIN55,212-2: ↓ proteoglycan and collagen degradation, iNOS, COX-2 expression, NFκB activation HU-210: ↓ proteoglycan and collagen degradation	[144]
WIN55,212-2 or CP55,940	IL-1β-stimulated RA and OA FLS	WIN55,212-2 and CP55,940: ↓ IL-6, IL-8 expression (not inhibited by CB1 nor CB2 antagonists)	[145]
A-796260	MIA-induced rat OA model	↑ grip force	[147]
4Q3C	CIA mouse model	↓ arthritis severity, histopathological changes, bone erosion, osteoclast formation ↓ RANKL/OPG ratio, TNFα, IL-1β, COX-2, NO expression	[131]
GW405833	MIA-induced rat OA model	Control animals: ↓ joint afferent firing rate OA animals: ↑ sensitization of mechanoreceptors (diminished by AM630 or SB366791), ↑ hindlimb incapacitance, ↑ CGRP release	[134]

Compound classification: 4Q3C: CB₂ agonist; A-796260: CB₂ agonist; A967079: TRPA1 antagonist; ACEA: CB₁ agonist; AM251: CB₁ antagonist; AM281: CB₁ antagonist; AM630: CB₂ antagonist; BAPTA: calcium chelating agent; COR170: CB₂ antagonist; CP55,940: nonselective CB agonist; GW405833: CB₂ agonist; HU-210: nonselective CB agonist; HU-308: CB₂ agonist; JTE907: CB₂ antagonist; JWH-015: CB₂ agonist; JWH-133: CB₂ agonist; metformin: AMPK activator; MJ15: CB₁ antagonist; rimonabant: CB₁ antagonist; SB366791: TRPV1 antagonist; SR144528: CB₂ antagonist; N55,212: nonselective CB agonist