Differential Response Properties of IB₄-Positive and -Negative Unmyelinated Sensory Neurons to Protons and Capsaicin

Abstract

Activation of unmyelinated (C-fiber) nociceptors by noxious chemicals plays a critical role in the initiation and maintenance of injury-induced pain. C-fiber nociceptors can be divided into two groups in which one class depends on nerve growth factor during postnatal development and contains neuropeptides, and the second class depends on glial cell line-derived neurotrophic factor during postnatal development and contains few neuropeptides but binds isolectin B(4) (IB(4)). We determined the sensitivity of these two populations to protons and capsaicin using whole cell recordings of dorsal root ganglion neurons from adult mouse. IB(4)-negative unmyelinated neurons were significantly more responsive to protons than IB(4)-positive neurons in a concentration-dependent manner. Approximately 86% of IB(4)-negative neurons responded to pH 5.0 with an inward current compared with only 33% of IB(4)-positive neurons. The subtypes of proton-evoked currents in IB(4)-negative unmyelinated neurons were also more diverse. Many IB(4)-negative neurons exhibited transient, rapidly inactivating proton currents as well as sustained proton currents. In contrast, IB(4)-positive neurons never displayed transient proton currents and responded to protons only with sustained, slowly inactivating inward currents. The two classes of neurons also responded differently to capsaicin. Twice as many naïve IB(4)-negative unmyelinated neurons responded to 1 microM capsaicin as IB(4)-positive neurons, and the capsaicin-evoked currents in IB(4)-negative neurons were approximately fourfold larger than those in IB(4)-positive neurons. Interestingly, proton exposure altered the capsaicin responsiveness of the two classes of neurons in opposite ways. Brief preexposure to protons increased the number of capsaicin-responsive IB(4)-positive neurons by twofold and increased the capsaicin-evoked currents by threefold. Conversely, proton exposure decreased the number of capsaicin-responsive IB(4)-negative neurons by 50%. These data suggest that IB(4)-negative unmyelinated nociceptors are initially the primary responders to both protons and capsaicin, but IB(4)-positive nociceptors have a unique capacity to be sensitized by protons to capsaicin-receptor agonists.

TRPV1 Function in Mouse Colon Sensory Neurons Is Enhanced by Metabotropic 5-Hydroxytryptamine Receptor Activation

“…This differs from results obtained in unidentified DRG neurons, in which Ͻ50% of cells responded to capsaicin (Dirajlal et al, 2003), consistent with studies showing mRNA or IR for TRPV1 in Ͻ50% of DRG neurons (Caterina et al, 1997;Michael and Priestley 1999;Robinson et al, 2004). Similarly, the response to acid appears to be distinct between identified visceral DRG neurons and unidentified DRG neurons.…”

“…A previous study of unidentified DRG neurons reported a mixture of transient and sustained acid-sensitive currents, both of which were significantly inhibited by amiloride (Dirajlal et al, 2003), suggesting a significant contribution of ASICs. In addition, the majority of the mouse colon DRG neurons in the present study responded to heat, whereas in a previous study only about half of unidentified DRG neurons were heat sensitive (Nagy and Rang, 1999).…”

Differential Responses of Bladder Lumbosacral and Thoracolumbar Dorsal Root Ganglion Neurons to Purinergic Agonists, Protons, and Capsaicin

“…More than 90% of bladder neurons responded to capsaicin with a sustained current, confirming the presence of functional TRPV1 receptors, which have been documented immunohistochemically (Cockayne et al, 2000;Birder et al, 2002). One might expect bladder neurons that responded to capsaicin to also exhibit a sustained current to protons, but neither we nor others (Steen et al, 1992;Dirajlal et al, 2003) found such a relationship. Both the sustained proton-evoked current and capsaicin-activated peak current densities were greater in LS than in TL neurons.…”

Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses

“…In a recent analysis of GDNFoverexpressing mice (Zwick et al, 2002), we found an increased number of IB4-positive neurons. Because these neurons are heat sensitive (Stucky and Lewin, 1999;Dirajlal et al, 2003), an increase in the number of TRPV1-positive neurons was also expected in these animals. However, no increase in the number of TRPV1 neurons was observed, and analysis of wild-type mice found that only 6% of mouse DRG neurons were positive for both IB4 and TRPV1 (Zwick et al, 2002).…”