Identifying unique subtypes of spinal afferent nerve endings within the urinary bladder of mice

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In visceral organs, sensory stimuli that reach noxious (painful) levels are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRG) (Gebhart, 2000; Gebhart & Bielefeldt, 2016; Kyloh, Nicholas, Zagorodnyuk, Brookes, & Spencer, 2011; Spencer, Kyloh, Beckett, Brookes, & Hibberd, 2016). Spinal afferents are not only of supreme importance to our understanding of visceral nociception, but these neurons also play a major role in detecting innocuous stimuli that underlie local neural reflexes that do not reach conscious sensation. Evidence that spinal afferents are essential for detection of painful stimuli has been provided by experiments where lesions are made to the spinal cord, which abolishes all sensations from visceral organs in the lower abdomen. Also, visceral nociceptive pathways underlying the visceromotor response have been shown to be abolished by lesions to spinal nerve pathways, including sensory reflex responses that are typically below the level of noxious sensation (Kyloh et al., 2011). There is some evidence that the vagus nerve can respond to noxious stimuli (Yu, Hu, & Yu, 2014). However, in general, the vagus nerve is thought to mediate largely nonnoxious stimuli (Phillips & Powley, 1998) and lesions to the vagus nerve do not block visceral pain, whereas lesions to spinal afferents abolishes all visceral sensation (including pain), even when vagal afferents are preserved (Kyloh et al., 2011). It is for this reason that there is significant interest in identifying the characteristics of spinal afferents and their nerve endings that transduce sensory stimuli into nerve action potentials. Although it is well understood that the cell bodies of spinal afferents are within DRG, the sites of innervation, morphology, and neurochemical coding of the peripheral nerve endings of spinal afferents that actually respond to sensory stimuli and transduce stimuli into action potentials are poorly understood. In fact, only recently have the characteristics of spinal afferents been uncovered. This is in direct contrast to vagal afferents, whose nerve endings are well characterized in most internal organs (Powley & Phillips, 2011; Powley, Spaulding, & Haglof, 2011).
Surprisingly, no studies that we are aware of have unequivocally identified the different morphological classes of spinal afferent endings in the urinary bladder of any species. This is likely due to a lack of techniques available that could selectively label only spinal afferents. In previous studies, peptidergic sensory nerves were visualized immunohistochemically (e.g., calcitonin‐gene‐related‐peptide [CGRP], Substance P, and capsaicin‐sensitive immunoreactive fibers) in the sub‐urothelium (consisting of the layer beneath the urothelium, including the lamina propria and submucosa) and in the muscle layers (Andersson, 2002; Avelino, Cruz, Nagy, & Cruz, 2002; Gabella & Davis, 1998; Rahnama'i et al., 2017). A number of studies have recorded from spinal afferents that innervate the urinary bladder and distinct firing patterns and responses to stimuli have been detected in a variety of species including cats (Habler, Janig, & Koltzenburg, 1993), guinea‐pigs (Zagorodnyuk, Costa, & Brookes, 2006; Zagorodnyuk, Gibbins, Costa, Brookes, & Gregory, 2007), rats (Shea, Cai, Crepps, Mason, & Perl, 2000), and mice (Xu & Gebhart, 2008).
However, unfortunately immunohistochemistry alone is insufficient to characterize the different morphological types of individual sensory nerve endings and cannot discriminate the origin of different types of peptidergic sensory fibers (e.g., spinal or vagal axons that express CGRP, or even some motor nerves that can express CGRP). Also, immunohistochemistry cannot readily identify nonpeptidergic sensory fibers and their endings due to a lack of reliable neurochemical markers for these nerves. To try to visualize nonpeptidergic sensory nerves and their endings, attempts were made to anterogradely label sensory endings in the bladder in vitro using biotinaminde (Zagorodnyuk, Brookes, & Spencer, 2010).
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