Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model

Abstract

Background and purpose: While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations.

Experimental approach: C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application.

Key results: JZL195 and the cannabinoid receptor agonist WIN55212 produced dose-dependent reductions in CCI-induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195-induced anti-allodynia was maintained during repeated treatment.

Conclusions and implications: These findings suggest that JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists.

Figure 1

Effect of CCI nerve injury on behavioural measures. Bar charts showing the effect of CCI versus sham surgery on raw values of (A) mechanical PWT, (B) acetone responses (Resp), (C) rotarod latency and (D) bar latency. *** and **** denote P < 0.001, 0.0001 for pre‐surgery versus post‐surgery.

Figure 2

Time course of WIN55212 and JZL195‐induced anti‐allodynia. Time plots of the effect of JZL195 (18 mg·kg⁻¹), WIN55212 (3 mg·kg⁻¹) and matched vehicle on (A) mechanical PWT and (B) rotarod latency. Animals received an s.c. injection at time 0 h, 7 days after CCI surgery (post‐CCI). The data for JZL195, WIN55212 and vehicle are also shown prior to CCI surgery (pre‐CCI). *, **, *** and **** denote P < 0.05, 0.01, 0.001 and 0.0001 compared with vehicle at the corresponding time points.

Figure 3

JZL195 reduces allodynia at doses below those at which it produces side effects. Dose response curves for the effect of JZL195 on (A) mechanical (Mech) PWT and acetone responses, (B) bar and rotarod latency, and (C) open field crossings. All data are expressed as a percentage of the maximum possible effect (% MPE), except open fields crossings for which raw data are shown (number of crossing over 2 min). The lines in (A) and (C) represent sigmoidal curve fits to the data.

Figure 4

WIN55212 reduces allodynia at similar doses to those at which it produces side effects. Dose response curves for the effect of WIN55212 on (A) mechanical (Mech) PWT and acetone responses, (B) bar and rotarod latency and (C) open field crossings. The lines in (A–C) represent sigmoidal curve fits to the data.

Figure 5

Comparison of the effect of maximal doses of endocannabinoid degradation inhibitors. Bar charts showing the effect of systemic administration of vehicle, or doses of URB597 (18 mg·kg⁻¹), JZL184 (18 mg·kg⁻¹) and JZL195 (18 mg·kg⁻¹) and WIN55212 (3 mg·kg⁻¹), which produced a maximal reduction in allodynia. Data are shown for (A) mechanical (Mech) PWT and acetones responses (Resp) (% MPE), (B) bar latency and rotarod latency (% MPE) and (C) open field crossings (number of grid crossing over 2 min). *, ** and **** denote P < 0.05, 0.01 and 0.0001 compared with vehicle; #, ##, ### and #### denote P < 0.05, 0.01, 0.001 and 0.0001 compared with JZL195.

Figure 6

The JZL195‐induced reduction in allodynia is maintained with repeated treatment. The effect of systemic injection of JZL195 (3, 18 mg·kg⁻¹) and vehicle on (A) mechanical PWT, (B) acetones responses (Resp), (C) bar latency, (D) rotarod latency and (E) open field crossing. Treatment with JZL195, or vehicle commenced at 7 days post‐CCI nerve injury, and was repeated for five consecutive days. In (A–D), data are shown for pre‐CCI nerve injury and pre‐injection and post‐injection on treatment days 1 and 5. In (E), raw open field data are shown for pre‐CCI nerve injury and post‐injection only on treatment days 1 and 50. In (A–D) *, **, *** and **** denote P < 0.05, 0.01, 0.001 and 0.0001 for pre‐drug versus post‐drug injection on days 1 and 5 of treatment; # denotes P < 0.05 for post‐injection day 5 versus day 1. In (E), ** denotes P < 0.01 for pre‐CCI versus post‐drug injection.