Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain

Abstract

Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6–S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain.

Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons

“…GBP can potently block TSP-induced formation of excitatory synapses (Dolphin, 2013; Eroglu et al, 2009; Hendrich et al, 2008). Additionally, GBP can modulate PKC signaling in the spinal cord dorsal horn (Yeh et al, 2011; Zhang et al, 2015) and regulate NMDA receptor function via PKC (Gu and Huang, 2001). Furthermore, activation of PKC can accelerate SERCA Ca 2+ uptake into ER (Usachev et al, 2006).…”

Bulleyaconitine A Exerts Antianxiety and Antivisceral Hypersensitivity Effects

“…Visceral pain is usually characterized by inaccurate localization and frequent referred pain (Zhang et al, 2015), which differs significantly in terms of neurological mechanisms. Visceral pain is one of the main causes for abdominal pain and has been an important biological hallmark of pain symptoms clinically (Keszthelyi et al, 2012;Hasler and Owyang, 2013;Camilleri, 2014;Wouters, 2014).…”

Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen)

“…Previously, some involvement of PKC in antinociceptive effects of gabapentin was reported in the trigeminal nucleus [33] and in spinal cord dorsal horn [34]. In a very recent report [35], this result was confirmed, with indirect evidence of the involvement of dorsal horn ε and γ PKC isoforms in a visceral pain model [36]. The western blot technique employed in those studies does not allow discrimination of the cell localization where PKC ε inhibition of translocation occurs, but a contribution of presynaptic PKC ε , present in the central terminal of the sensory neuron, consistent with the one we report here, is largely possible.…”