Antinociceptive activities of lidocaine and the nav1.8 blocker a803467 in diabetic rats

Abstract

The streptozocin-induced diabetic rat is a model of chronic pain that shows signs of hyperalgesia and allodynia and may replicate signs in diabetic humans. Here we investigated the antinociceptive effects of A803467, a highly selective blocker of Nav1.8 channels, in diabetic rats with painful neuropathy. We systemically (intraperitoneal) or locally (intraplantar) administered A803467 (or lidocaine, a nonselective sodium channel blocker, as a control) to diabetic rats with hyperalgesia and allodynia and then measured thermal latencies and mechanical thresholds. With intraperitoneal administration, A803467 led to 6-fold greater reduction of hyperalgesia and 2-fold greater reduction of allodynia than did lidocaine. Whereas the antihyperalgesic effects of lidocaine and A803467 were similar after intraplantar administration, A803467 (1 mg) was at least 2 times more effective as an antiallodynic than was lidocaine (0.5 mg). These results suggest that compared with lidocaine, systemic or local blockade of Nav1.8 channels by A803467 may more effectively relieve hyperalgesia and allodynia in diabetic neuropathy.

Figure 1.

General metabolic indicators of saline-treated (nondiabetic) and STZ-treated rats. (A) Blood glucose levels were elevated after treatment with STZ compared with those in nondiabetic rats. (B) STZ induction caused significant decreases in body weight. Each point represents the mean value of 7 rats, and the vertical bars indicate 1 SD. *, Significant (P < 0.05; repeated-measures ANOVA and the posthoc Dunn test) differences between diabetic and nondiabetic groups.

Figure 2.

Paw withdrawal latency after thermal stimulus. Antihyperalgesic effects of intraperitoneal administration of A803467 and lidocaine to (A) diabetic and (B) nondiabetic rats. (C) Time course of thermal hyperalgesia after STZ treatment. Each point represents the mean value of 7 rats, and the vertical bars indicate 1 SD. D, time of drug injection; arrow, pretreatment value; *, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values of DMSO only and saline groups at each time point; #, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values after 10 mg/kg A803467 and 10 mg/kg lidocaine at each time point.

Figure 3.

Changes in mechanical threshold to mechanical stimulus. Antiallodynic efficacies of intraperitoneal administration of A803467 and lidocaine to (A) diabetic and (B) nondiabetic rats. (C) Time course of mechanical allodynia after STZ treatment. Each point represents the mean value of 7 rats, and the vertical bars indicate 1 SD. D, time of drug injection; arrow, pretreatment value; *, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values of DMSO only and saline groups at each time point; #, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values after 10 mg/kg A803467 and 10 mg/kg lidocaine at each time point.

Figure 4.

Effects of intraplantar A803467 and lidocaine on thermal hyperalgesia in diabetic (A) and nondiabetic rats (B). Each point represents the mean value of 7 rats, and the vertical bars indicate the SD. D, time of drug injection; arrow, pretreatment value; *, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values of DMSO only and saline groups at each time point.

Figure 5.

Antiallodynic effects of intraplantar A803467 and lidocaine in (A) diabetic and (B) nondiabetic rats. Each point represents the mean value of 7 rats, and the vertical bars indicate the SD; D, time of drug injection; arrow, pretreatment value; *, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values of DMSO only and saline groups at each time point; #, significant (P < 0.05; Kruskal–Wallis repeated-measures ANOVA with Dunn multiple-comparison tests) difference from values after 1 mg/kg A803467 and 1 mg/kg lidocaine at each time point.