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Anesthesiology:
doi: 10.1097/ALN.0b013e3181fe400b
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Molecular Mechanism of Cross-organ Reflex Sensitization: Should I Pay Attention to It?

Zuo, Zhiyi M.D., Ph.D.*; Sorkin, Linda S. Ph.D.†

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THE cross-organ reflex, especially among pelvic organs, is a well-known phenomenon. Such reflexes do not require conscious input although they play a critical role in many basic daily activities, such as urination and fecal and urinary continence.1 However, these physiologically important reflexes can be deleteriously enhanced when an organ receives strong or chronic stimulation. Thus, stimulation to one organ can lead to abnormal function or sensitivity in another organ. This phenomenon is called cross-organ reflex sensitization.1,2
Neural structures are essential for maintaining cross-organ reflexes. One postulated mechanism is viscero-visceral convergence on spinal neurons in the lumbosacral enlargement.3 Neurons with these dual inputs are also implicated in the development of cross-organ reflex sensitization. However, very little is known about the intraneuronal molecular mechanism for cross-organ reflex sensitization. In this issue of Anesthesiology, Peng et al.4 present data to suggest that redistribution of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the extrasynaptic plasma membrane of neurons in the lumbosacral spinal cord dorsal horn is important for the development of capsaicin-induced colon-urethra cross-organ reflex sensitization in rats.
Peng et al.4 performed a comprehensive study defining intracellular signal transduction cascades in dorsal horn cells involved in this process. They recorded urethral sphincter electromyograms in response to electrical stimulation of the pelvic nerve in female rats. In parallel, they measured protein redistribution of the AMPA receptor subunits (glutamate receptors 1 and 2, GluR1 and GluR2), protein kinase A (PKA), and A-kinase anchor protein to the plasma membrane of cells in the lumbosacral dorsal horn. When capsaicin, an irritant, was administered to the descending colon, an increased urethral response to pelvic nerve stimulation was observed, suggesting that capsaicin induced a colon-urethra cross-organ reflex sensitization. They also found that capsaicin application increased the amount of PKA, A-kinase anchor protein, and GluR1 in the plasma membrane as well as GluR1 phosphorylated at serine 845, the phosphorylation site by PKA,5 in whole-tissue homogenates. Equally important was the lack of change in the amount of membrane GluR2 and total (membrane + cytosolic) GluR1. Taken together, these results indicate movement of new AMPA receptors into the plasma membrane, resulting in increased AMPA-receptor density and neuronal sensitization. Although not mentioned by the authors, the lack of change in membrane GluR2 indicates that the new AMPA receptors are relatively permeable to Ca2+ and, thus, are even more likely to participate in sensitization and pain behavior.6,7 By using a comprehensive pharmacologic approach involving agonists and antagonists to multiple elements of the cascade, in tandem with RNA interference to silence A-kinase anchor protein expression, the authors provide solid evidence to suggest that N-methyl-d-aspartate–initiated PKA phosphorylation of GluR1 via an A-kinase anchor protein linkage and downstream redistribution of GluR1 subunit to the plasma membrane are necessary for the development of colon-urethra cross-organ reflex sensitization. Although not clearly proven in this paper, their data suggest that PKA phosphorylation of GluR1 is necessary for GluR1 insertion into the plasma membrane.
One major discovery in neuroscience in recent years is the identification of the role of AMPA receptor trafficking in the synaptic plasticity. Synaptic strengthening and plasticity are fundamental processes for many basic neurologic functions, such as learning and memory, as well as pathologic conditions, including neuropathic pain.8,9 It has been convincingly shown that AMPA receptor trafficking to the plasma membrane is needed for the development of long-term potentiation,10 an electrophysiologic form of learning and memory, in the hippocampus. It is noteworthy that several of these studies have demonstrated that many of the “new” AMPA receptors in the membrane do not contain GluR2, implying that they are permeable to Ca2+.11,12 Subsequent studies have shown that PKA-dependent phosphorylation of serine 845 in GluR1 induced by N-methyl-d-aspartate–receptor activation is critical for the trafficking of GluR1 to the plasma membrane of hippocampal neurons.5,13,14 Others15,16 have shown that enhanced pain behavior and spinal cord dorsal horn neuronal sensitization resulting from cutaneous injection of capsaicin or of other inflammatory mediators are also dependent on PKA phosphorylation of GluR1 serine 845 as well as on trafficking of GluR1 into the plasma membranes. Peng et al.4 have now expanded our knowledge of AMPA receptor biology by showing that trafficking is important in the development of another form of dorsal horn plasticity, cross-organ reflex sensitization. This mechanism may underlie the persistent hyperexcitability of neurons in the lumbosacral spinal cord with convergent colon-bladder input seen after colonic inflammation reported by Foreman's group.2
The findings of Peng et al.4 may have significant implications in the clinical practice of anesthesiology if their results are confirmed in human studies. Cross-organ reflex sensitization may play a role in many pathologic conditions, such as chronic pelvic pain and referred pain—common clinical problems.2,17 Cross-organ reflex sensitization may also be a pathophysiologic process for the dysfunction of multiple organs in a disease. For example, patients with irritable bowel syndrome often have urinary urgency.18 Various proteins in the signaling pathway identified by Peng et al.4 may be therapeutic targets for these human diseases or conditions. Consistent with this idea, AMPA receptor redistribution to the plasma membrane has been shown to be involved in modulation of pain behavior in animals.15
However, we are still far away from developing therapeutic interventions for human use based on the findings of Peng et al.4 First, findings from animal studies need to be confirmed in humans. Second, Peng et al.4 used inhibitors for various proteins before capsaicin application to block cross-organ reflex sensitization. It will be important to know whether cross-organ reflex sensitization can be blocked by those inhibitors used after capsaicin application or even after the reflex sensitization is established because a patient often seeks medical attention after symptoms are manifested. Third, the toxicity of those inhibitors in humans will need to be tested carefully. Along this line, Peng et al.4 showed that injection of lidocaine into the colon before capsaicin application blocked capsaicin-induced cross-organ reflex sensitization. It would have been useful to determine the effects of intrathecal lidocaine or other local anesthetics on the cross-organ reflex sensitization because intrathecal or intraepidural injection of local anesthetics has been safely used in clinical practice for years.
Zhiyi Zuo, M.D., Ph.D.,*
Linda S. Sorkin, Ph.D.†
*Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia. zz3c@virginia.edu.
†Department of Anesthesiology, University of California, San Diego, La Jolla, California.
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