JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy

Iryna Khasabova, Xu Yao, Justin Paz, Cutler T. Lewandowski, Amy E. Lindberg, Lia Coicou, Natasha Burlakova, Donald A Simone, Virginia S Seybold

Research output: Contribution to journalArticle

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Abstract

Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1 mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.

Original languageEnglish (US)
Pages (from-to)67-75
Number of pages9
JournalPharmacological Research
Volume90
DOIs
StatePublished - Jan 1 2014

Fingerprint

Peripheral Nervous System Diseases
Cisplatin
Hyperalgesia
Spinal Ganglia
Cannabinoid Receptor CB2
Endocannabinoids
Skin
Cannabinoid Receptor CB1
Injections
Cannabinoids
JZL 184
Chronic Pain
2-arachidonylglycerol
Hydrolysis
Therapeutics
Enzymes

Keywords

  • 2-Arachidonoyl-glycerol
  • Anandamide
  • Cannabinoid receptor
  • Cisplatin
  • Dorsal root ganglion
  • Hyperlagesia
  • JZL184
  • Spinal cord

Cite this

JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. / Khasabova, Iryna; Yao, Xu; Paz, Justin; Lewandowski, Cutler T.; Lindberg, Amy E.; Coicou, Lia; Burlakova, Natasha; Simone, Donald A; Seybold, Virginia S.

In: Pharmacological Research, Vol. 90, 01.01.2014, p. 67-75.

Research output: Contribution to journalArticle

Khasabova, I, Yao, X, Paz, J, Lewandowski, CT, Lindberg, AE, Coicou, L, Burlakova, N, Simone, DA & Seybold, VS 2014, 'JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy', Pharmacological Research, vol. 90, pp. 67-75. https://doi.org/10.1016/j.phrs.2014.09.008
Khasabova, Iryna ; Yao, Xu ; Paz, Justin ; Lewandowski, Cutler T. ; Lindberg, Amy E. ; Coicou, Lia ; Burlakova, Natasha ; Simone, Donald A ; Seybold, Virginia S. / JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. In: Pharmacological Research. 2014 ; Vol. 90. pp. 67-75.
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abstract = "Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1 mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.",
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AU - Yao, Xu

AU - Paz, Justin

AU - Lewandowski, Cutler T.

AU - Lindberg, Amy E.

AU - Coicou, Lia

AU - Burlakova, Natasha

AU - Simone, Donald A

AU - Seybold, Virginia S

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AB - Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1 mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [3H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [3H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.

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