Attenuation of mouse somatic and emotional inflammatory pain by hydralazine through scavenging acrolein and inhibiting neuronal activation.

BACKGROUND Acrolein signaling is important during spinal cord injury; whether it is involved in somatic and emotional pain is not clear. Hydralazine is a potent antihypertensive drug and can scavenge acrolein efficiently. OBJECTIVE We hypothesized that hydralazine decreases spinal level acrolein and renders analgesic effects with some side effects, which was tested in the current study. STUDY DESIGN Subcutaneous injection of formalin was used to induce somatic and emotional pain responses. The spinal neuronal activation (FOS expression) and acrolein expression were evaluated at 2 hours after subcutaneous formalin injection. The possible side effects of hydralazine on the murine central nervous system or cardiovascular system were evaluated at one hour after hydralazine injection with open field, elevated plus maze and rotarod tests, or telemetrical measurement of mean artery blood pressure and heart rate. RESULTS The subcutanous injection of formalin into the left hind paw induced significant somatic and emotional pain responses, evaluated by the biphasic spontaneous flinch/licking of the injected hind paw and interphase ultrasonic vocalizations during the one hour window after formalin injection. The spinal acrolein level was significantly increased and neurons were activated at 2 hours after formalin injection. Intraperitoneal injection of hydralazine (at 0.1, 1 or 10 mg/kg of body weight) at one hour before formalin challenging dose-dependently attenuated the formalin induced pain responses with an analgesic 50% effect dose ranging from 0.2 to 1 mg/kg of body weight. Furthermore, the neuronal activation and elevated acrolein expression were dose-dependently inhibited by hydralazine pretreatment. The side effects of intraperitoneal hydralazine on locomotion, anxiety, and motor coordination at one hour after hydralazine administration had negative results. The main side effects of hydralazine were an insignificant decrease of blood pressure and a significant increase of heart rates at high dose (10 mg/kg of body weight). LIMITATIONS This study is limited because the analgesic effect of hydralazine was tested on only one type of acute inflammatory pain model; however, its effect on chronic inflammatory or neuropathic pain needs to be further investigated. CONCLUSIONS Based on the above findings, hydralazine may find its new application of analgesia within a safe dose window (around one mg/kg of body weight) without causing severe side effects.