Partial sciatic nerve ligation leads to an upregulation of Ni2+-resistant T-type Ca2+ currents in capsaicin-responsive nociceptive dorsal root ganglion neurons.

BACKGROUND: Neuropathic pain resulting from peripheral nerve lesions is a common medical condition, but current analgesics are often insufficient. The identification of key molecules involved in pathological pain processing is a prerequisite for the development of new analgesic drugs. Hyperexcitability of nociceptive DRG-neurons due to regulation of voltage-gated ion-channels is generally assumed to contribute strongly to neuropathic pain. There is increasing evidence, that T-type Ca2+-currents and in particular the Cav3.2 T-type-channel isoform play an important role in neuropathic pain, but experimental results are contradicting. PURPOSE: To clarify the role of T-type Ca2+-channels and in particular the Cav3.2 T-type-channel isoform in neuropathic pain. METHODS: The effect of partial sciatic nerve ligation (PNL) on pain behavior and the properties of T-type-currents in nociceptive DRG-neurons was tested in wild-type and Cav3.2-deficient mice. RESULTS: In wild-type mice, PNL of the sciatic nerve caused neuropathic pain and an increase of T-type Ca2+-currents in capsaicin-responsive neurons, while capsaicin-unresponsive neurons were unaffected. Pharmacological experiments revealed that this upregulation was due to an increase of a Ni2+-resistant Ca2+-current component, inconsistent with Cav3.2 up-regulation. Moreover, following PNL Cav3.2-deficient mice showed neuropathic pain behavior and an increase of T-Type Ca2+-currents indistinguishable to that of PNL treated wild-type mice. CONCLUSION: These data suggest that PNL induces an upregulation of T-Type Ca2+-currents in capsaicin-responsive DRG-neurons mediated by an increase of a Ni2+-insensitive current component (possibly Cav3.1 or Cav3.3). These findings provide relevance for the development of target specific analgesic drugs.

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na+ current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na+ currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na+ channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals.

The transcription factor Smad-interacting protein 1 controls pain sensitivity via modulation of DRG neuron excitability.

The perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by primary nociceptive neurons. The molecular mechanisms that orchestrate the expression and function of ion channels relevant for pain processing are poorly understood. We demonstrate here a central role of the transcription factor Smad-interacting protein 1 (Sip1/Zfhx1b/Zeb2), a 2-handed zinc finger DNA-binding protein with essential functions in neural crest and forebrain development, in controlling nociceptive neuron excitability and pain sensitivity. Mutant mice lacking 1 Zfhx1b allele displayed decreased thermal pain responses, whereas mechanical pain was unaffected. In parallel, repetitive firing of capsaicin/heat-sensitive nociceptive DRG neurons was markedly impaired. Analysis of the voltage-gated currents underlying repetitive firing revealed a significant increase in persistent sodium currents and a reduction in delayed rectifier potassium currents. Modeling experiments in conjunction with experimental results suggest that these changes cause a depolarization-induced block of action potential propagation past the DRG axon T-junction. These data suggest that Sip1 controls the transduction properties of heat-sensitive primary sensory neurons and thus thermal pain sensitivity in a novel manner via coordinated changes in DRG-neuron voltage-gated ion channels.