The role of l-arginine/NO/cGMP/KATP channel pathway in the local antinociceptive effect of berberine in the rat formalin test

Berberine is an isoquinoline alkaloid naturally produced by several types of plants. Berberine has extensive pharmacological effects, such as anti-diabetic, anti-inflammatory, and antioxidant effects. In the current study, we assess the antinociceptive effects of berberine and its association with the l-arginine (l-Arg)/NO/cGMP/KATP channel pathway via intraplantar administration in rats. To examine the antinociceptive properties of berberine, the formalin test was conducted. The number of rat paw flinches was counted for an h. l-Arg (precursor of nitric oxide, 3–30 μg/paw), l-NAME (NO synthase inhibitor, 10 and 100 μg/paw), methylene blue (guanylyl cyclase inhibitor, 100 and 200 μg/paw), and glibenclamide (ATP-sensitive potassium channel blocker, 10 and 30 μg/paw) were locally injected, respectively, into the right hind paws of rats as a pre-treatment before berberine injection to understand how the l-Arg/NO/cGMP/KATP pathway plays a role in the antinociceptive effect of berberine. The ipsilateral injection of berberine into the right paw (0.1–100  μg/paw) showed a dose-dependent antinociceptive effect in both the first and second phases of the formalin test, almost similar to morphine (25 μg/paw). Intraplantar injection of l-Arg (30 µg/paw) increased the antinociceptive effect of berberine in the second phase. In addition, injection of l-NAME, methylene blue, and glibenclamide caused a reduction in the antinociceptive effect of berberine throughout the second phase in a dose-dependent manner. However, the antinociceptive effects of berberine in the first phase of the rat formalin test were not affected by this pathway. As a novel local antinociceptive agent, berberine can exert a peripheral antinociceptive effect via the l-Arg/NO/cGMP/KATP channel pathway.