The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy

Abstract

Background and purpose: Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB(1)) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects.

Experimental approach: The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain.

Key results: Systemically administered L-29 (10 mg kg(-1)) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg(-1)). The CB(1) receptor antagonist SR141716a (1 mg kg(-1)) and the CB(2) receptor antagonist SR144528 (1 mg kg(-1)) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-alpha antagonist, MK-886 (1 mg kg(-1)), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg(-1)) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity.

Conclusions and implications: L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation.

Figure 1

The effect of L-29 (1–20 mg kg⁻¹) on hindpaw reflex behaviours in PSNI-treated rats. Hindpaw withdrawal thresholds to (a) thermal (b) mechanical and (c) a cooling stimulus in PSNI rats treated with L-29 (1–20 mg kg⁻¹) vs vehicle control (n=12 per group). Statistical significance of differences between each dose and the vehicle control (^*P<0.01) was determined by a one-way ANOVA with Dunn's all pairwise multiple comparisons or (^§P<0.01) between each post-injection value vs the pre-injection values (at time 0) using a one way ANOVA with Dunnett's multiple comparisons vs control post hoc analysis. Each value is the mean±s.e.m. ANOVA, analysis of variance; PSNI, partial sciatic nerve injury.

Figure 2

The dose response of L-29 on hindpaw reflex behaviours in partial sciatic nerve injury-treated rats. Dose response curves for the effect of L-29 on hindpaw withdrawal responses to (a) thermal (at 40 min post-injection), (b) mechanical (at 20 min post-injection) and (c) a cold (40 min post-injection) stimulus. The time point with the largest effect of L-29 for each modality was chosen and values determined as % change from pre-injection value. In all modalities, 10 mg kg⁻¹ is the optimum dose.

Figure 3

The effect of L-29 (10 mg kg⁻¹) on hindpaw hypersensitivity to a mechanical stimulus in ddC- and VZV-treated rats. Hindpaw withdrawal thresholds in response to mechanical stimulation in (a) ddC-treated rats at day 19 post-initial treatment (n=12) and (b) VZV-treated rats at day 14 post-treatment (n=10) following L-29 (10 mg kg⁻¹) or vehicle control. Statistical significance of differences between L-29 and vehicle control values (^*P<0.01) was determined by a one-way ANOVA with Dunn's all pairwise multiple comparisons or (^§P<0.01) between each post-injection value vs the pre-injection values (at time 0) using a one way ANOVA with Dunnett's multiple comparisons vs control post hoc analysis. Each value is the mean±s.e.m. ANOVA, analysis of variance; ddC, dideoxycitadine; VZV, varicella zoster virus.

Figure 4

The effect of gabapentin (50 mg kg⁻¹) vs L-29 (10 mg kg⁻¹) on hindpaw reflex behaviours in PSNI-, ddC- and VZV-treated rats. Hindpaw withdrawal thresholds to (a) thermal or (b) mechanical stimulus in PSNI rats treated (c) mechanical stimulus in ddC-treated rats and (d) mechanical stimulus in VZV-treated rats following injection with L-29 (10 mg kg⁻¹) or gabapentin (50 mg kg⁻¹) (n=12 per group). Statistical significance of differences (^*P<0.01) of each drug vs vehicle control or (^§P<0.05) between L-29 vs gabapentin was determined by a one-way ANOVA with Dunn's all pairwise multiple comparisons post hoc analysis. Each value is the mean±s.e.m. ANOVA, analysis of variance; ddC, dideoxycitadine; PSNI, partial sciatic nerve injury; VZV, varicella zoster virus.

Figure 5

The effect of the cannabinoid antagonists SR141716a and SR144528 on the response to L-29 in PSNI-, ddC- or VZV-treated rats. Hindpaw withdrawal thresholds to (a) thermal or (b) mechanical stimulus in PSNI rats; (c) mechanical stimulus in ddC-treated rats and (d) mechanical stimulus in VZV-treated rats, following injection with L-29 (10 mg kg⁻¹) or SR141716A (1 mg kg⁻¹)+L-29 (10 mg kg⁻¹) or SR144528 (1 mg kg⁻¹)+L-29 (10 mg kg⁻¹) (n=10 per group). The statistical significance of difference (^*P<0.05) between drug and vehicle control or (^#P<0.05) the antagonist and L-29 was determined by a one-way ANOVA with Dunn's all pairwise multiple comparisons post hoc analysis. Each value is the mean±s.e.m. ANOVA, analysis of variance; ddC, dideoxycitadine; PSNI, partial sciatic nerve injury; VZV, varicella zoster virus.

Figure 6

The effect of the PPAR-α antagonist MK-886 on the response to L-29 in PSNI-treated rats. Hindpaw withdrawal thresholds to (a) thermal or (b) mechanical stimulus in PSNI rats treated following injection with L-29 (10 mg kg⁻¹) or MK-886 (1 mg kg⁻¹)+L-29 (10 mg kg⁻¹) (n=10 per group). The statistical significance of difference (^*P<0.01) between drug and vehicle control or (^#P<0.01) L-29+MK-886 and L-29 was determined by a one-way ANOVA with Dunn's all pairwise multiple comparisons post hoc analysis. Each value is the mean±s.e.m. ANOVA, analysis of variance; PSNI, partial sciatic nerve injury; PPAR, peroxisome proliferator-activated receptor-α.

Figure 7

The effect of L-29 (10 mg kg⁻¹) on altered spontaneous exploratory activity in the open field arena in rats 7 days following PSNI. (a) The number of entries into the inner zone (40 × 40 cm) and (b) time spent in the inner zone of the open field arena was significantly reduced in rats 7 days following PSNI treatment as compared to sham (n=10 per group). This reduction was reversed in animals treated with L-29 (10 mg kg⁻¹) 20 min before the test as compared to vehicle-treated rats. (c) The total distance moved within the open field arena (1 × 1 m) was assessed over 15 min and is not significantly different between sham control animals, vehicle-treated PSNI animals or L-29-treated PSNI animals. The statistical significance of differences from the vehicle control group (^*P<0.05) was determined using a one way ANOVA with Dunn's all pairwise multiple comparisons. Each value is the mean±s.e.m. (d, e) Example traces of (d) vehicle-treated and (e) L-29-treated PSNI rats over 15 min in the open field arena. ANOVA, analysis of variance; PSNI, partial sciatic nerve injury.