TY - JOUR
T1 - Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy
AU - Khasabova, Iryna A.
AU - Khasabov, Sergey
AU - Paz, Justin
AU - Harding-Rose, Catherine
AU - Simone, Donald A.
AU - Seybold, Virginia S.
PY - 2012/5/16
Y1 - 2012/5/16
N2 - Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30 - 40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 d, we investigated the anti-hyperalgesic effects of anandamide (AEA) and cyclohexylcar-bamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597), an inhibitor of AEA hydrolysis. Cisplatin-induced mechanical and heat hyperalgesia were accompanied by a decrease in the level of AEA in plantar paw skin. No changes in motor activity were observed after seven injections of cisplatin. Intraplantar injection of AEA (10/μg/10/μl) or URB597 (9μg/10μl) transiently attenuated hyperalgesia through activation of peripheral CB 1 receptors. Co-injections of URB597 (0.3 mg/kg daily, i.p.) with cisplatin decreased and delayed the development of mechanical and heat hyperalgesia. The effect of URB597 was mediated by CB1 receptors since AM281 (0.33 mg/kg daily, i.p.) blocked the effect of URB597. Co-injection of URB597 also normalized the cisplatin-induced decrease in conduction velocity of Aα/Aβ-fibers and reduced the increase of ATF-3 and TRPV1 immunoreactivity in dorsal root ganglion (DRG) neurons. Since DRGs are a primary site of toxicity by cisplatin, effects of cisplatin were studied on cultured DRG neurons. Incubation of DRG neurons with cisplatin (4 μg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB 1 receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.
AB - Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30 - 40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 d, we investigated the anti-hyperalgesic effects of anandamide (AEA) and cyclohexylcar-bamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597), an inhibitor of AEA hydrolysis. Cisplatin-induced mechanical and heat hyperalgesia were accompanied by a decrease in the level of AEA in plantar paw skin. No changes in motor activity were observed after seven injections of cisplatin. Intraplantar injection of AEA (10/μg/10/μl) or URB597 (9μg/10μl) transiently attenuated hyperalgesia through activation of peripheral CB 1 receptors. Co-injections of URB597 (0.3 mg/kg daily, i.p.) with cisplatin decreased and delayed the development of mechanical and heat hyperalgesia. The effect of URB597 was mediated by CB1 receptors since AM281 (0.33 mg/kg daily, i.p.) blocked the effect of URB597. Co-injection of URB597 also normalized the cisplatin-induced decrease in conduction velocity of Aα/Aβ-fibers and reduced the increase of ATF-3 and TRPV1 immunoreactivity in dorsal root ganglion (DRG) neurons. Since DRGs are a primary site of toxicity by cisplatin, effects of cisplatin were studied on cultured DRG neurons. Incubation of DRG neurons with cisplatin (4 μg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB 1 receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.
UR - http://www.scopus.com/inward/record.url?scp=84861122636&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861122636&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0403-12.2012
DO - 10.1523/JNEUROSCI.0403-12.2012
M3 - Article
C2 - 22593077
AN - SCOPUS:84861122636
SN - 0270-6474
VL - 32
SP - 7091
EP - 7101
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 20
ER -