Inhibitors of G-proteins and protein kinases reduce the sensitization to mechanical stimulation and the desensitization to heat of spinothalamic tract neurons induced by intradermal injection of capsaicin in the primate

Abstract

Intradermal injection of capsaicin results in sensitization of spinothalamic tract cells to brushing and pressure applied to the cutaneous receptive field in anesthetized monkeys. A significant increase in background activity also occurs immediately after capsaicin injection that lasts for at least 2 h. A 40-50% decrease in the response to noxious heat stimuli is also observed following capsaicin injection. This study investigated the spinal role of second messengers by extracellularly recording from spinothalamic tract cells and delivering inhibitors of second messenger pathways to the spinal cord by microdialysis. Blockade of protein kinases with the general protein kinase inhibitor, H7 (5.0 mM, n = 6), reduced the sensitization of the cells to brush and pressure. Blockade of protein kinase C with NPC15437 (10.0 mM, n = 10) reduced the increased background activity and the increased responses to brush. Blockade of protein kinase A with H89 (0.01 mM, n = 9) was most effective. H89 reduced the background activity, the increased responses to brush and press, and reversed the decreased response to noxious heat stimuli. Blockade of G-proteins with the general G-protein inhibitor, GDP-beta-S (1.0 mM, n = 9), reduced the background activity and the responses to brush and pressure without affecting the decreased response to heat. Thus, multiple intracellular messengers appear to be involved in the processing of central sensitization induced by activation of C-fibers following intradermal injection of capsaicin.

Enhanced Phosphorylation of NMDA Receptor 1 Subunits in Spinal Cord Dorsal Horn and Spinothalamic Tract Neurons after Intradermal Injection of Capsaicin in Rats

“…and , by influx of Ca 2ϩ through NMDA channels and voltage-gated calcium channels (Sluka, 1997) and by activation of excitatory G-protein-coupled membrane receptors, such as neurokinin-1 receptors (Dougherty et al, 1994) and group I metabotropic glutamate receptors (Neugebauer et al, 1999). This results in the activation of signal transduction cascades in these neurons (Lin et al, 1996(Lin et al, , 1997aSluka et al, 1997). The present study shows that NR1 subunits of NMDA receptors in STT cells are then phosphorylated, presumably by PKA.…”

“…This time course parallels closely that of the secondary mechanical allodynia observed in human subjects . Central sensitization of STT cells depends on the activation of several protein kinases (PKs), including PKC, PKG, and PKA (Lin et al, 1996(Lin et al, , 1997aSluka et al, 1997). Similarly, PKC and PKA have been shown to produce a long-lasting enhancement of excitatory responses of dorsal horn neurons in in vitro preparations Huang, 1991, 1992;Cerne et al, 1992Cerne et al, , 1993Rusin et al, 1993).…”

Protein Kinases Mediate Increment of the Phosphorylation of Cyclic AMP -Responsive Element Binding Protein in Spinal Cord of Rats following Capsaicin Injection

“…In experimental animals with capsaicin injection induced-central sensitization, activation of the PKA or the PKC pathways by their activators enhanced the response of spinothalamic (STT) cells to mechanical stimuli [15,19] and inhibitors of PKA or PKC blocked the hypersensitivity of STT neurons. Experiments from behavioral studies also support the roles of PKA and PKC in the generation of spinal cord central sensitization [2,15,19]. Our study further demonstrates the roles of PKA and PKC in molecular mechanism of regulation of gene transcription in response to capsaicin injection, in which they mediate the phosphorylation of the transcription factor, CREB.…”

“…As we previously reported [25], the concentrations of NPC15473 and H89 were 20 mM and 10 μM, respectively. The specificity of the inhibitors was previously reported [5,19,25]. All of the agents were infused for 30 min.…”

Temporal regularity determines the impact of electrical stimulation on tactile reactivity and response to capsaicin in spinally transected rats

“…For example, peripheral treatment with the TRPV1 agonist capsaicin enhances pain reports in humans (Simone et al, 1989; LaMotte et al, 1992) and tactile reactivity in animals (Baumann et al, 1991; Sluka et al, 1997; Kim et al, 2007). Research suggests that enhanced pain is due, in part, to the sensitization of nociceptive systems within the spinal cord, a phenomenon known as central sensitization (Woolf and Salter, 2000; Latremoliere and Woolf, 2009).…”