The Central Role of Glia in Pathological Pain and the Potential of Targeting the Cannabinoid 2 Receptor for Pain Relief

Table 1

CB₂R agonist effects from animal and clinical studies. For the compound/produced by column, *indicates compounds that are also examined in clinical trials. For the CB₂R > CB₁R selective column, human binding (h), rat binding (r). For in vivo models of pain, the abbreviations are as follows: local inflammatory pain models of lipopolysaccharide (LPS), complete Freund’s adjuvant (CFA). The systemic visceral model of pain: intraperitoneal acetic acid (i.p. acetic acid). Neuropathic pain models: chronic constriction injury (CCI), sciatic nerve ligation (SNL), intraperitoneal chemotherapy-induced pain (i.p. paxlitaxol), bone cancer-induced pain (bone cancer), osteoarthritis induction via knee joint synovium injection (knee joint osteoarthritis). Other models of pain utilized are noted as: postoperative model of surgical pain (PSP) and intrathecal administration of the HIV-1 envelope glycoprotein, gp120 (i.t. gp120).

Compound/produced by	Classification	CB2R > CB1R selective	CB2R compound route of administration	In Vivo models of pain	Tested efficacy	Glial effects	References
A-796260; Abbott Laboratories	Alkylindole	h = 206-fold; r = 26-fold	i.p.	CFA, CCI, PSP, Knee joint osteoarthritis	Mechanical allodynia, Grip force	Unknown	[182–184]
A-836339; Abbott Laboratories	Aminothiazole	h = 421-fold; r = 189-fold	i.p., plantar hindpaw, intra-DRG, i.t.	CFA, CCI, PSP	Thermal hyperalgesia, mechanical allodynia	Unknown	[167, 182–184]
AM1241; Cayman Chemicals, Sigma-Aldrich, Enzo Life Sciences, A. Makryannis (Northeastern University)	Amino-alkylindole	h = 125-fold; r = 36-fold protean agonist	i.p., i.t., intra-DRG, plantar hindpaw	Bone cancer, SNL, CCI	Mechanical allodynia, thermal hyperalgesia	↓ astrocyte activation	[157, 161–163, 167–169]
AM1710; A. Makryannis (Northeastern University)	Cannabilactone	r = 57-fold	i.t., i.p.	i.p. paxlitaxol, CCI, i.t. gp120	Mechanical allodynia, thermal hyperalgesia	Prevented macrophages/microglial mediated induction of i.t. gp120	[157, 168, 169, 176, 177, 179]
AM1714; A. Makryannis (Northeastern University)	Cannabilactone	r = 490-fold	i.p.	i.p. paxlitaxol	Mechanical allodynia, thermal hyperalgesia	Unknown	[157, 176, 178]
*Cannabinor; Pharmos Scientific	Bicyclic	h ~ 80–90-fold	i.p., oral, s.c.	Hindpaw carrageenan, i.p. acetic acid, CCI	Thermal hyperalgesia, mechanical allodynia, cold allodynia	Unknown	[156, 189, 190]
CBS0550; S. Saito (Taisho Pharmaceutical Co.)	Imine Derivative	h = 1000-fold	oral	Hindpaw yeast cell wall	Mechanical hyperalgesia	Unknown	[186]
*GRC10693; Glenmark Pharmaceutical Limited	Unknown	Species unknown >4700-fold	oral	CFA, CCI, SNL	Unknown	Unknown	Glenmark Pharmaceuticals website
GW405833; Sigma-Adrich, Tocris Bioscience, Santa Cruz Biotechnology Inc, Enzo Life Sciences	Amino-alkylindole	h = 1200-fold r=78-fold	i.p., chronic i.p.	SNL, CCI, Knee joint osteoarthritis	Mechanical allodynia	↓ astrocyte activation, ↓ microglial activation	[170, 171, 173]
*GW842166X; Glaxo-Smith-Klein	Pyrimidine Ester	h ~ 500-fold	Oral	CFA	Paw weight bearing	Unknown	[191]
JWH-015; Cayman Chemicals, Sigma-Aldrich, Tocris Bioscience	Amino-alkylindole	h = 27-fold	Plantar hindpaw, i.t.	CCI, PSP	Thermal hyperalgesia, mechanical allodynia, cold allodynia	↓ microglial activation, ↓ astrocyte activation i.t., prevented microglial activation (in vitro)	[93, 158, 159, 192]
MDA19; M. Naguib (University of Texas)	N-alkyl isatin acylhydrazone derivative	h ~ 14-fold; r ~ 70 fold protean agonist	i.p.	SNL, i.p. paxlitaxol	Mechanical allodynia	Unknown	[181]
O-3223; A. Lichtman (Virginia Commonwealth University)	Ethyl Sulfonamide derivative of THC	h = 80-fold	i.p.	LPS, SNL	Edema, thermal hyperalgesia	Unknown	[185]