Although this discusses visceral afferent (pain) signals, the nerves also contain efferent fibers that send signals to the organs. The correlation between visceral pain fibers and onset of pathology may be overlooking the 'silent' effects of efferent fiber miscoding that over time precipitate frank, painful, visceral pathologies. Nonetheless this paper demonstrated that nerve signal miscoding may initiate the disease process. Pain signals are easy to study and evaluate. As are muscle contractions from somatic efferent activity. The visceral efferents convey information to the organs to maintain homeostasis. When pressure on a nerve causes miscoding, organ function will not be optimal. Over time this may be instrumental in initiating visceral pain and disease. There is no easy way to study this, yet. Visceral (organ) pain fibers detect stretching of the organ sheath from swelling. The efferents affect what happens inside the organ.
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"In this chapter, we will discuss recent findings regarding the anatomy and physiology of visceral afferents and how these discoveries may lead to new treatments for visceral pain. In addition, we will discuss exciting new studies that suggesthyperactive visceral nociceptors might not only mediate persistent visceral pain, but that they may actually drive the initial visceral disease processes."
"In cancer patients, the level of TRPV1 mRNA was positively correlated with their reported pain scores; however, the same observation was not made among pancreatitis patients. Underlying this difference might be the expression of TRPV1 on the cancer cells themselves, as observed histologically. Treatment of pancreatic cancer cell lines with resiniferotoxin (RTX), which binds TRPV1 and ablates sensory neurons, reduced cancer cell growth and induced apoptosis above what was observed following treatment with chemotherapeutic agents (Hartel et al. 2006)."
Note: Could the RTX toxin be blocking aberrant efferent signals, as well?
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Julie A. Christianson and Brian M. Davis.
Go to:3.1. INTRODUCTIONVisceral pain is the number one reason for patient visits in the United States. In many cases, visceral pain is not associated with obvious pathology. For example, irritable bowel syndrome (IBS), which can occur following inflammation (Gwee et al. 1996; Collins et al. 1999; Bercik et al. 2005), is a diagnosis of exclusion because its hallmarks include abdominal pain accompanied by diarrhea or constipation in the absence of any obvious pathophysiology. It has been proposed that one of the contributing factors to these persistent pain states is chronic hypersensitivity of visceral sensory neurons (Wood 2002; Cenac et al. 2007).
Afferents innervating somatic tissue, such as skin, muscle, or bone, can be categorized based on their response properties to stimulation. Large, myelinated afferents generally mediate information related to proprioception and light touch or vibration, whereas small, thinly myelinated or unmyelinated afferents, commonly termed nociceptors, detect noxious or potentially damaging stimuli, including thermal, high-threshold mechanical and chemical stimuli. This is in contrast to the sensory innervation of the viscera, which is mostly made up of small, thinly myelinated or unmyelinated afferents that display low mechanical thresholds, enabling them to code normal physiological stimuli (i.e., non-noxious), as well as an ability to code stimuli in the noxious range (Sengupta and Gebhart 1994a, 1994b; Wood 2002; Cenac et al. 2007). Thus, if one uses a functional definition for nociceptors (i.e., the ability to code noxious stimuli), most visceral afferents would be classified as nociceptors. To further separate themselves from somatic afferents, which receive sensory innervation only from neurons located in the dorsal root ganglia (DRG), visceral structures from the esophagus to the transverse colon are innervated not only by DRG located in the cervical, thoracic, and upper lumbar regions, but also by sensory neurons arising from the superior and inferior vagal ganglia (jugular and nodose ganglia, respectively; Figure 3.1) (Ricco et al. 1996; Undem et al. 2004; Yu et al. 2005; Zhong et al. 2008). Visceral structures located distal to the transverse colon, particularly the distal colon, rectum and bladder are also innervated by two populations of afferents; however, these are both of spinal origin arising from two different levels of the spinal cord (thoracolumbar and lumbosacral; Figure 3.1) (de Groat 1987; Keast and de Groat 1992; Wang et al. 1998; Traub et al. 1999; Christianson et al. 2006a, 2007). Sensory neurons arising from these two spinal locations appear to convey different aspects of the complex sensation that humans identify as visceral pain. The functional difference between these populations is not as obvious as that between vagal and spinal afferents, but evidence suggests that they may differentially respond to injury and disease (Traub 2000; Traub and Murphy 2002; Lin and Al-Chaer 2003).
FIGURE 3.1Vertebral distribution of visceral afferents innervating different organs. Sensory neurons innervating visceral structures in the mouse were retrogradely labeled using Alexa fluor-conjugated cholera toxin β(CTB) and the distribution of afferents (more...)
In this chapter, we will discuss recent findings regarding the anatomy and physiology of visceral afferents and how these discoveries may lead to new treatments for visceral pain. In addition, we will discuss exciting new studies that suggest hyperactive visceral nociceptors might not only mediate persistent visceral pain, but that they may actually drive the initial visceral disease processes.
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As noted in the Introduction, recent studies have implicated changes in visceral afferents as not only responsible for ongoing visceral pain but also in a role of initiating or contributing to disease progression. Some of the best examples come from studies of pancreatic diseases including diabetes, pancreatic cancer, and pancreatitis. In all of these cases the evidence points to a central role for TRPV1-expressing pancreatic afferents. For example, TRPV1 mRNA levels were significantly increased in pancreata from patients suffering from either pancreatic cancer or pancreatitis, compared to healthy control tissue (Hartel et al. 2006). In cancer patients, the level of TRPV1 mRNA was positively correlated with their reported pain scores; however, the same observation was not made among pancreatitis patients. Underlying this difference might be the expression of TRPV1 on the cancer cells themselves, as observed histologically. Treatment of pancreatic cancer cell lines with resiniferotoxin (RTX), which binds TRPV1 and ablates sensory neurons, reduced cancer cell growth and induced apoptosis above what was observed following treatment with chemotherapeutic agents (Hartel et al. 2006). It has long been known that pancreatic tumors are accompanied by hypertrophy of pancreatic nerve bundles, which is likely due to the reported increased production of neurotrophic factors (including nerve growth factor [NGF] and artemin) that occurs in cancerous pancreata (Zhu et al. 1999, 2001; Okada et al. 2004; Ito et al. 2005; Ceyhan et al. 2006; Ma et al. 2008). Receptors for these growth factors are expressed on the same neurons that express TRPV1 and TRPA1 (Orozco et al. 2001; Elitt et al. 2006; Malin et al. 2006; Malin et al. 2009), and brief exposure of NGF or artemin can potentiate TRPV1 and TRPA1 function in dissociated neurons (Malin et al. 2006). The hypertrophied nerve bundles in combination with potentiated TRPV1 and TRPA1 likely contribute to the intense pain that accompanies most pancreatic cancers. In addition, the hypertrophied nerve bundles have been shown to form a conduit on which tumor cells travel to metastasize to adjacent organs (Ceyhan et al. 2006). This observation has led to the proposal that sprouting and hypertrophy of neuronal processes is the third leg of a metastatic triad, also including proliferation of blood and lymphatic vessels, which serves to promote survival and spread of tumor cells (Ceyhan et al. 2008b, 2008a; Schneider et al. 2008).
Evidence that visceral afferents contribute to the development of disease via their efferent function (e.g., via peripheral release of peptides) comes from studies of pancreatitis and diabetes. Animal models of acute pancreatitis have demonstrated that afferents expressing TRPV1 are essential for the onset and maintenance of pancreatitis and associated pain. TRPV1 mRNA and protein expression were both increased in pancreatic DRG neurons in a rat model of chronic pancreatitis, and treatment with TRPV1 antagonist has been shown to reduce both visceral and referred somatic pain behaviors (Xu et al. 2007). Ablation of the TRPV1-positive afferent fibers by either neonatal capsaicin treatment (Nathan et al. 2002) or via resiniferatoxin (Noble et al. 2006; Romac et al. 2008) significantly reduced substance P release and pancreatic inflammation and/or prevented the development of pancreatitis. It is important to note that the expression of TRPV1 is not required for afferent-induced pancreatic inflammation, as mice lacking functional TRPV1 developed pancreatitis similar to control mice (Xu et al. 2007). The efferent functions of the afferent, as well as the expression of other receptors, is sufficient for the initiation and maintenance of pancreatitis. PAR2, previously mentioned for its role in IBS, is activated endogenously by release of trypsin or tryptase, both of which are increased in pancreatitis (Namkung et al. 2008). PAR2 activation has been shown to sensitize TRPV1 in vitro (Hoogerwerf et al. 2001) and has been implicated in pancreatitis (Hoogerwerf et al. 2004; Kawabata et al. 2006; Ishikura et al. 2007; Laukkarinen et al. 2008; Namkung et al. 2008).
Another intriguing observation implicating efferent function of primary afferents in visceral disease comes from studies of a mouse model of type 1 diabetes (Razavi et al. 2006). In diabetes-prone non-obese diabetic (NOD) mice, islet inflammation develops spontaneously as the animal ages, leading to insulin resistance, degeneration of the pancreas, and early mortality. Ablation of TRPV1-positive fibers with neonatal capsaicin blocks the development of islet inflammation and abnormal glucose regulation. However, the exact role of these afferents in disease progression is complicated. The nod locus that is responsible for development of diabetes contains TRPV1, and TRPV1 function in these mice is reduced both with respect to capsaicin-induced currents and amount of mRNA produced. Moreover, infusion of substance P, which would normally be released by the TRPV1-expressing afferents, also prevents progression of diabetes. Thus, the diabetic phenotype in these mice can be reversed by either ablating the defective fibers or replacing the neuroactive peptide (SP) that these fibers would normally release. These data indicate that these fibers are intimately involved in pancreatic health. The authors of this report suggest that the apparently conflicting results can be explained by the need for a balance between inflammatory β-cells and primary afferents. This balance is disrupted in the NOD mice by the TRPV1 hypomorph and can be restored by either ablation of these fibers or by restoration of SP levels in the pancreas (Razavi et al. 2006). Clearly, more work needs to be done, but these results are exciting inasmuch as they open up a completely new way to treat a complicated and debilitating disease.
Go to:3.5. SUMMARYVisceral afferents have received significantly less attention than their somatic counterparts. This is in large part because they have been more difficult to study due to their small numbers and inaccessibility. However, development of new anatomical, physiological, and molecular techniques has made it possible to examine these neurons at the same level of detail as other sensory neurons. The changes that occur in visceral afferents not only play central roles in the development of chronic pain states, but in some cases they may initiate or maintain disease states, as well. Phenotypic characterization of visceral neurons is already well underway, and initial studies have identified unique neurochemical properties, which might make them attractive targets for new pharmacological approaches. Potential treatment options may pharmacologically silence specific visceral afferents or, in extreme cases, ablate pathological neurons while leaving the sensory neurons that are required for maintaining homeostasis untouched.
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