Analgesic effects of the COX-2 inhibitor parecoxib on surgical pain through suppression of spinal ERK signaling.

Cyclooxygenase (COX)-2 inhibitors are widely used for postoperative pain control in clinical practice. However, it is unknown whether spinal sensitization is involved in the analgesic effects of COX-2 inhibitors on surgical pain. Extracellular signal-regulated kinase (ERK) in the spinal cord is implicated in various types of pain, including surgical pain. The present study investigated the role of spinal ERK signaling in the analgesic effect of the COX-2 inhibitor parecoxib on surgical pain. Surgical pain was produced in rats by surgical incision of the hind paw. Phosphorylated (p)-ERK1/2 expression was determined by immunohistochemistry. Pain hypersensitivity was evaluated by measuring the paw withdrawal threshold using the von Frey test. The selective COX-2 inhibitor parecoxib was delivered 20 min before or 20 min after the incision by intraperitoneal injection. Pretreatment with parecoxib markedly attenuated the pain hypersensitivity induced by incision. However, post-treatment with parecoxib produced minimal analgesic effects. Parecoxib inhibited the increase in spinal p-ERK expression following surgical incision. The present study thus suggests that the COX-2 inhibitor parecoxib exerts its analgesic effect on surgical pain through the inhibition of neuronal ERK activation in the spinal cord. COX-2 inhibitor delivery prior to surgery has more potent analgesic effects, suggesting the advantage of preventive analgesia for post-operative pain control.

Activation of spinal ERK1/2 contributes to mechanical allodynia in a rat model of postoperative pain.

Extracellular signal­regulated kinase (ERK) 1/2 in the spinal cord has been implicated in the development of neuropathic pain and inflammatory pain. However, a limited number of studies have investigated the role of spinal ERK in incisional pain. The present study aimed to determine the role of ERK in the spinal cord in incisional pain. Incisional pain was established in rats by a unilateral hind paw incision. ERK1/2 expression was analyzed by immunohistochemistry. Hypersensitivity to pain was evaluated by measuring the paw withdrawal threshold using the von Frey test. The mitogen­activated protein kinase kinase (MEK) inhibitor, U0126, was administered 20 min prior to or 10 min following the incision by intrathecal or intraperitoneal injection. Phosphorylated ERK1/2 in the ipsilateral L4­5 spinal superficial dorsal horn was activated 1 min following the incision, reached its peak level at 5 min and then returned to the basal level 20 min following the incision. Pretreatment, but not post­treatment with U0126 markedly attenuated the pain hypersensitivity induced by the incision. Therefore, the present study indicates that the transient activation of spinal ERK1/2 contributes to the initiation of pain hypersensitivity following surgical incision.

Biphasic activation of extracellular signal-regulated kinase in anterior cingulate cortex distinctly regulates the development of pain-related anxiety and mechanical hypersensitivity in rats after incision.

BACKGROUND: A recent study has demonstrated that surgical incision induces an anxiety-like behavior but its relationship with incision-evoked mechanical hypersensitivity remains elusive. Extracellular signal-regulated kinase (ERK) activity in the anterior cingulate cortex (ACC) is important for the affective pain. The current study aims to explore ERK1/2 activity in the ACC and its role in the development of anxiety and mechanical hypersensitivity after incision. METHODS: Anxiety-like behavior was measured by elevated plus maze experiment and open field test after hind paw incision. ERK1/2 phosphorylation was determined by immunohistochemistry and Western blot. Cannulae were implanted into the bilateral ACC for the intra-ACC injection of ERK inhibitors PD98059 and U0126. Brushing (innocuous stimulus) was used to investigate its effect on ERK activation under the incision-evoked painful condition. RESULTS: The anxiety-like behavior induced by the hind paw incision persisted longer than mechanical hypersensitivity. One hind paw incision resulted in a biphasic ERK activation in bilateral ACC. Inhibiting ERK activation in the early phase attenuated pain-related anxiety and mechanical hypersensitivity whereas inhibiting ERK activation in the late phase only reduced the anxiety-like behavior. During the time interval between two phases of ERK activation, brushing the incised skin dramatically increased ERK phosphorylation in the ACC. CONCLUSIONS: These data suggest that in the early phase of postoperative pain, pain-related anxiety and mechanical hypersensitivity are tightly linked and regulated by the ERK activation in the ACC. However, in the late phase of postoperative pain, ERK activation in the ACC is only required for the expression of pain-related anxiety but not mechanical hypersensitivity.