Involvement of the Heme-Oxygenase Pathway in the Antiallodynic and Antihyperalgesic Activity of Harpagophytum procumbens in Rats

Abstract

Harpagophytum procumbens (H. procumbens), also known as Devil's Claw, has been used to treat a wide range of pathological conditions, including pain, arthritis and inflammation. Inflammatory mediators, released at the site of injury, can sensitize nociceptive terminals and are responsible for allodynia and hyperalgesia. Carbon monoxide (CO), produced in a reaction catalyzed by the enzyme heme oxygenase (HO), may play a role in nociceptive processing and has also been recognized to act as a neurotransmitter or neuromodulator in the nervous system. This study was designed to investigate whether the HO/CO pathway is involved in the analgesic response of H. procumbens in carrageenan-induced hyperalgesia in rats. Mechanical allodynia and thermal hyperalgesia were evaluated by using von Frey filaments and the plantar test, respectively. The results of our experiments showed that pretreatment with the HO inhibitor ZnPP IX significantly decreased the antihyperalgesic effect produced by H. procumbens (800 mg/kg, i.p.) in carrageenan-injected rats. Consistently, the pretreatment with hemin, a HO-1 substrate, or CORM-3, a CO releasing molecule, before a low dose of H. procumbens (300 mg/kg, i.p.) induced a clear antiallodynic response in carrageenan injected rats. These results suggest the involvement of HO-1/CO system in the antiallodynic and antihyperalgesic effect of H. procumbens in carrageenan-induced inflammatory pain.

Keywords: Harpagophytum procumbens; allodynia; carbon monoxide; carrageenan; hyperalgesia; rat.

Figure 1

(A) Effect of H. procumbens (300 and 800 mg/kg i.p.), injected before i.pl. carrageenan (2%/0.1 mL/rat), on mechanical allodynia. Mechanical thresholds were measured with von Frey’s filaments. Results are expressed in grams (g) and represent the means ± SEM from 8 to 10 rats. # p < 0.05 vs. saline treated-rats; * p < 0.05 vs. carrageenan injected-rats; (B) Effect of H. procumbens (300 and 800 mg/kg i.p.), injected before i.pl. carrageenan (2%/0.1 mL/rat), on thermal hyperalgesia. Thermal thresholds were measured with Plantar test. Results are expressed in seconds (s) and represent the means ± SEM from 8 to 10 rats. # p < 0.05 vs. saline treated-rats; * p < 0.05 vs. carrageenan injected-rats.

Figure 2

(A) Effect of the pretreatment with ZnPP IX (1 mg/kg s.c.) on the antiallodynic effect of H. procumbens (800 mg/kg i.p.) in carrageenan-injected rats (2%/0.1 mL/rat). Mechanical thresholds were measured with von Frey’s filaments. Results are expressed in grams (g) and represent the means ± SEM from 8 to 10 rats. * p < 0.05 vs. carrageenan injected-rats; # p < 0.05 vs. saline treated-rats; ** p < 0.05 vs. H. procumbens + carrageenan treated-rats; (B) Effect of the pretreatment with ZnPP IX (1 mg/kg s.c.) on the antihyperalgesic (panel B) effect of H. procumbens (800 mg/kg i.p.) in carrageenan-injected rats (2%/0.1 mL/rat). Thermal thresholds were measured with Plantar test. Results are expressed in seconds (s) and represent the means ± SEM from 8 to 10 rats. * p < 0.05 vs. carrageenan injected-rats; # p < 0.05 vs. saline treated-rats; ** p < 0.05 vs. H. procumbens + carrageenan treated-rats.

Figure 3

(A) Effect of the pretreatment with hemin (0.5 mg/kg s.c.) on the antiallodynic effect of H. procumbens (300 mg/kg i.p.) in carrageenan-injected rats (2%/0.1 mL/rat). Mechanical thresholds were measured with von Frey’s filaments. Results are expressed in grams (g) and represent the means ± SEM from 8 to 10 rats. # p < 0.05 vs. saline treated-rats; § p < 0.05 vs. carrageenan injected-rats; (B) Effect of the pretreatment with hemin (0.5 mg/kg s.c.) on the antihyperalgesic effect of H. procumbens (300 mg/kg i.p.) in carrageenan-injected rats (2%/0.1 mL/rat). Thermal thresholds were measured with Plantar test. Results are expressed in seconds (s) and represent the means ± SEM from 8 to 10 rats. # p < 0.05 vs. saline treated-rats; § p < 0.05 vs. carrageenan injected-rats.

Figure 4

(A) Effect of the pretreatment with CORM 3 (3.0 mg/kg i.p.) on the antiallodynic effect of H. procumbens (300 mg/kg i.p.) in carrageenan-injected rats (2%/0.1 mL/rat). Mechanical thresholds were measured with von Frey’s filaments. Results are expressed in grams (g) and represent the means ± SEM from 8 to 10 rats. # p < 0.05 vs. saline treated-rats; § p < 0.05 vs. carrageenan injected-rats; (B) Effect of the pretreatment with CORM 3 (3.0 mg/kg i.p.) on the antihyperalgesic effect of H. procumbens (300 mg/kg i.p.) in carrageenan-injected rats (2%/0.1 mL/rat). Thermal thresholds were measured with Plantar test. Results are expressed in seconds (s) and represent the means ± SEM from 8 to 10 rats. # p < 0.05 vs. saline treated-rats; § p < 0.05 vs. carrageenan injected-rats.