Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain N. Schuelert, C. Zhang, A.J. Mogg, L.M. Broad,

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Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain N. Schuelert, C. Zhang, A.J. Mogg, L.M. Broad, D.L. Hepburn, E.S. Nisenbaum, M.P. Johnson, J.J. McDougall Osteoarthritis and Cartilage Volume 18, Issue 11, Pages 1536-1543 (November 2010) DOI: 10.1016/j.joca.2010.09.005 Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Colocalization of CB2 and TRPV1 antibodies in sham-injected control rat DRG cells (A–C) and synovial membrane (D–F). CB2 (green: A) and TRPV1 (red: B) antibody staining is evident in the lumbar DRG cells. CB2 staining is evident in small, medium and large diameter DGR cells, whereas TRPV1 expression is primarily in small- and medium-sized cells. Merged images (C) indicate colocalization of CB2 and TRPV1 in small to medium-sized cells (open arrows). Examples of large diameter DRG neurons positively labeled with CB2 only are also shown (arrow heads). Scale bars=100μm. In the synovial membrane, CB2 (green: D) and TRPV1 (red: E) antibody staining is evident. Merged images (F) indicate colocalization of CB2 and TRPV1 antibody labeling in synoviocytes (open arrows). Scale bars=50μm. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Effect of GW405833 on control knee joints. (A) Specimen recording of a single unit during rotation of a control knee joint before and after close intra-arterial application of GW405833. GW405833 significantly reduced the firing rate of joint afferent nerve fibres. (B) The effect of GW405833 on knee joint afferent nerve mechanosensitivity in response to rotation of saline-injected knee joints. The desensitizing effect of GW405833 was dose-dependent and significantly different from the effect of vehicle control treatment [P<0.0001 by two-way ANOVA (n=22–27 fibres)]. Values are the mean of all time points with 95% CIs. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Effect of GW405833 on osteoarthritis (OA) joints. (A) Specimen recording of a single unit during rotation of an OA knee joint before and after close intra-arterial application of GW405833. GW405833 significantly sensitized the firing rate of joint afferent nerve fibres. (B) The effect of GW405833 on knee joint afferent nerve mechanosensitivity in response to rotation of OA knee joints. The sensitising effect of GW405833 was dose-dependent and significantly different from the effect of vehicle control treatment [P<0.0001 by two-way ANOVA (n=24–28 fibres)]. Values are the mean of all time points with 95% CIs. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 (A) Effect of co-administration of the CB2 receptor antagonist AM630 with GW405833 (10−8mol) on control (saline-injected) knee joints. The CB2 antagonist AM630 significantly reduced the desensitizing effect of GW405833; one-way ANOVA with Bonferroni’s multiple comparison test. (B) In the OA joint GW405833 causes significant sensitization compared to the vehicle. This GW405833-mediated sensitization was blocked by co-administration of AM630 or by pre-administration of the TRPV1 receptor antagonist SB366791; one-way ANOVA with Bonferroni’ s multiple comparison test. When administered alone, AM630 or SB366791 had no significant effect on joint mechanosensitivity. Values are the mean of all time points with 95% CIs of 12–28 fibres. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Effect of intra-articular injection of GW405833 (10−6mol) on hindpaw weight distribution in control and OA joints, compared to vehicle injection. In control joints, GW405833 had no significant effect on weight distribution compared to naive rats. In OA rats, following GW405833 injection, body weight was redistributed onto the non-injected contralateral hindlimb while co-administration of the CB2 receptor antagonist AM630 or pre-administration of the TRPV1 receptor antagonist SB366791 attenuated this GW405833 induced weight-bearing deficit. The algesic effect of GW405833 was maximal 60min after injection. Bonferroni’s multiple comparison test; n=8 animals/group. Data are means with 95% CIs. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 Concentration–response curves for the effect of GW405833 on CGRP release from adult rat spinal cord. GW405833 assayed alone under basal (open squares) conditions of the TRPV1 channel no CGRP release was observed. After phosphorylation of the TRPV1 channel (solid triangles) CGRP release was significantly increased (two-way ANOVA P<0.001). Each data point represents mean CGRP release with 95% CIs expressed as a percent of capsaicin and buffer controls. n=3. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions

Supplementary Fig. 1: Colocalization of CB2 and TRPV1 antibodies in MIA-treated rat DRG cells (A–C) and synovial membrane (D–F). CB2 (green: A) and TRPV1 (red: B) antibody staining is evident in the lumbar DRG cells. CB2 staining is evident in small, medium and large diameter DGR cells, whereas TRPV1 expression is primarily in small- and medium-sized cells. Merged images (C) indicate colocalization of CB2 and TRPV1 in small to medium-sized cells (open arrows). Examples of large diameter DRG neurons positively labeled with CB2 only are also shown (arrow heads). Scale bars=100μm. In the synovial membrane, CB2 (green: D) and TRPV1 (red: E) antibody staining is evident. Merged images (F) indicate colocalization of CB2 and TRPV1 antibody labeling in synoviocytes (open arrows). Scale bars=50μm. Osteoarthritis and Cartilage 2010 18, 1536-1543DOI: (10.1016/j.joca.2010.09.005) Copyright © 2010 Osteoarthritis Research Society International Terms and Conditions