Key Publications


Nociceptor Sensitization

By the mid 90’s it was clear that changes in the intrinsic properties of nociceptors was responsible for the sensitization that underlies injury-induced pain and hypersensitivity. It was still unknown, however, which ion channel(s) was responsible for the increase in excitability. We discovered that a tetrodotoxin (TTX) resistant voltage gated sodium current (TTX-R INa), subsequently identified as NaV1.8, was the likely culprit. Our work revealed that it is ideally distributed among sensor neurons (with an expression pattern largely restricted to nociceptive afferents), has biophysical properties consistent with an essential role on the control of nociceptive afferent excitability, and was acutely modulated by an array of inflammatory mediators in a manner consistent with a role in sensitization. We subsequently demonstrated that the channel serves as a point of convergence for distinct second messenger signaling pathways. Finally, our work showed for the first time that this channel is essential for inflammatory mediator-induced hypersensitivity as well as the manifestation of neuropathic pain. NaV1.8 remains promising target for the treatment of pain.

Gold MS, Dastmalchi S, Levine JD (1996a) Co-expression of nociceptor properties in dorsal root ganglion neurons from the adult rat in vitro. Neuroscience 71:265-275.

Gold MS, Reichling DB, Shuster MJ, Levine JD (1996b) Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A 93:1108-1112.

Gold MS, Levine JD, Correa AM (1998) Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons In vitro. J Neurosci 18:10345-10355.

Gold MS, Weinreich D, Kim CS, Wang R, Treanor J, Porreca F, Lai J (2003) Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci 23:158-166.

Factors accounting for the complexity of pain

There are still no consistently effective treatments for pain devoid of deleterious consequences. A focus of our work has been on the identification of factors that could account for this dearth of therapeutic options. Our work has revealed that different types of injury cause nociceptor sensitization through different mechanisms. These findings illustrate that the type of injury, time after injury, sex homoneses, and the target of innervation all impact the mechanism of sensitization, highlighting the complexity of pain mechanisms and the potential need for tailored therapies depending on the type of injury.

Zhang X-L, Mok L, Charbonnet M, Lee K-Y, Gold MS (2012) Inflammation-induced changes in BKCa currents in cutaneous dorsal root ganglion neurons from the adult rat. Mol Pain 8.

Flake NM, Lancaster E, Weinreich D, Gold MS (2004) Absence of an association between axotomy-induced changes in sodium currents and excitability in DRG neurons from the adult rat. Pain 109:471-480.

Flake NM, Bonebreak DB, Gold MS (2005) Estrogen and inflammation increase the excitability of rat temporomandibular joint afferent neurons. J Neurophysiol 93:1585-1597.

Vaughn AH, Gold MS (2010) Ionic mechanisms underlying inflammatory mediator-induced sensitization of dural afferents. J Neurosci 30:7878-7888.

Nociceptor properties

While the initial characterization of nociceptive afferents indicated that there was heterogeneity among nociceptive afferents, investigators and clinicians continue to use relatively crude criteria, such as peptide content and conduction velocity, to identify the subpopulations of neurons studied, if they use any criteria at all. However, it is essential to characterize the properties and distribution of proteins of interest among nociceptive afferents before we can begin to assess the relative contribution of these proteins to injury-induced changes in afferent properties. To address this key gap, we performed a detailed characterization of voltage-gated K+ currents among sensory neurons, Ca2+-dependent K+ channels, receptors and Ca2+ regulatory proteins. These studies serve as a critical foundation upon which to identify mechanisms underlying injury-induced plasticity in sensory neurons.

Gold MS, Shuster MJ, Levine JD (1996) Characterization of six voltage-gated K+ currents in adult rat sensory neurons. J Neurophysiol 75:2629-2646.

Zhang XL, Mok LP, Katz EJ, Gold MS (2010) BK(Ca) currents are enriched in a subpopulation of adult rat cutaneous nociceptive dorsal root ganglion neurons. Eur J Neurosci 31:450-462.

Zhu Y, Dua S, Gold MS (2012) Inflammation-induced shift in spinal GABA(A) signaling is associated with a tyrosine kinase-dependent increase in GABA(A) current density in nociceptive afferents. J Neurophysiol 108:2581-2593.

Scheff NN, Yilmaz E, Gold MS (2014) The properties, distribution and function of Na(+)-Ca(2+) exchanger isoforms in rat cutaneous sensory neurons. J Physiol 592:4969-4993.

Regulation of intracellular Ca2+ in nociceptive afferents

Intracellular Ca2+ transients transients are often used an indirect measure of neural activity. However, we have not only documented the heterogeneity of Ca2+ regulatory proteins among sensory neurons, but have demonstrated that after the initial increase in intracellular Ca2+ associated with membrane depolarization-induced activation of voltage-gated Ca2+ channels, the amplitude and duration of the subsequent Ca2+ transient in nociceptive afferents has little to do with the change in membrane potential.  Furthermore, there are micro/sub-domains of Ca2+ regulation even detectable in the isolated cell body that serve to functionally isolate one source of Ca2+ from another. Through this line of investigation we were able to identify the mechanism underlying the inflammation-induced increase in the duration of depolarization-evoked Ca2+ transients in the isolated afferent cell body of a subpopulation of putative nociceptive afferents. Interestingly, this change was due to a unidirectional increase in trafficking of the Na+/Ca2+ exchanger (NCX) to the site of inflammation. The result would be a decrease in transmitter release in the periphery, altered Ca2+ transients at the cell body (which should result in changes in gene expression), and an increase in transmitter releases at the central terminal (which should contribute to inflammatory hypersensitivity). These results not only highlight the complexity of Ca2+ signaling in nociceptive afferents, but the potential contribution of changes in Ca2+ regulatory mechanisms to injury-induced pain and hypersensitivity.

Lu SG, Zhang X, Gold MS (2006) Intracellular calcium regulation among subpopulations of rat dorsal root ganglion neurons. J Physiol 577:169-190.

Lu SG, Gold MS (2008) Inflammation-induced increase in evoked calcium transients in subpopulations of rat dorsal root ganglion neurons. Neuroscience 153:279-288.

Scheff NN, Lu SG, Gold MS (2013) Contribution of endoplasmic reticulum Ca2+ regulatory mechanisms to the inflammation-induced increase in the evoked Ca2+ transient in rat cutaneous dorsal root ganglion neurons. Cell Calcium 54:46-56.

Scheff NN, Gold MS (2015) Trafficking of Na+/Ca2+ exchanger to the site of persistent inflammation in nociceptive afferents. J Neurosci 35:8423-8432.

Dynamic interplay between ion channels in nociceptive afferents

The identification of pain patients with mutations in ion channels such as NaV1.7 that are distributed throughout the peripheral nervous system that have suffer from highly localized episodic pain attacks, suggests that the relative impact of any given ion channel on the excitability of a neuron is going to depend on the relative density, distribution and biophysical properties of the other ion channels (and Ca2+ regulatory mechanisms) present in the neuron. We have provided direct evidence for this idea. For example, persistent inflammation-induced sensitization of masseter muscle afferents is associated with the down-regulation of an inactivating voltage-gated K+ channel, but this sensitization in cutaneous neurons is associated with a decrease in Ca2+-dependent K+ channels secondary to a decrease in voltage-gated Ca2+ current. More interestingly, the GABAA-receptor mediated excitation of cutaneous afferents requires this down-regulation of K+ current. In marked contrast, inflammatory mediator-induced sensitization of dural afferents is dependent on the activation of a Cl- current that is able to sensitize dural afferents because of the properties of and changes in the other channels present.

Harriott AM, Dessem D, Gold MS (2006) Inflammation increases the excitability of masseter muscle afferents. Neuroscience 141:433-442.

Zhu Y, Lu SG, Gold MS (2012) Persistent inflammation increases GABA-induced depolarization of rat cutaneous dorsal root ganglion neurons in vitro. Neuroscience 220:330-340.


Complete List of Published Work in MyBibliography