Activity-dependent slowing properties of an unmyelinated low threshold mechanoreceptor in human hairy skin.

It has been previously shown that unmyelinated afferent fibres in human skin are differentiated not only by their receptor characteristics, but also by their profiles of activity-dependent slowing. One type of profile, described originally as 'type 3', is different from that of nociceptors (type 1), cold afferents (type 2) and sympathetic efferents (type 4), in that these fibres display a minimal activity-dependent slowing (∼1% at 2 Hz). However, their function remains to be determined. Here we describe one unit with a typical 'type 3' activity-dependent slowing profile recorded from an undamaged fascicle of the superficial peroneal nerve of a patient. Its conduction velocity was 1.8 m s(-1) and it slowed by 1.3% during the 2 Hz tetanus. This unit had a mechanical receptive field in the hairy skin and responded readily to weak mechanical stimuli, and not to cold. This suggests that the low threshold unmyelinated mechanoreceptors recently described in human hairy skin are probably endowed with a 'type 3' activity-dependent profile.

A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome.

OBJECTIVE: Although the term 'reflex sympathetic dystrophy' has been replaced by 'complex regional pain syndrome' (CRPS) type I, there remains a widespread presumption that the sympathetic nervous system is actively involved in mediating chronic neuropathic pain ["sympathetically maintained pain" (SMP)], even in the absence of detectable neuropathophysiology. METHODS: We have used microneurography to evaluate possible electrophysiological interactions in 24 patients diagnosed with CRPS I (n=13), or CRPS II (n=11) by simultaneously recording from single identified sympathetic efferent fibers and C nociceptors, while provoking sympathetic neural discharges in cutaneous nerves. RESULTS: We assessed potential effects of sympathetic activity upon 35 polymodal nociceptors and 19 mechano-insensitive nociceptors, recorded in CRPS I (26 nociceptors) and CRPS II patients (28 nociceptors). No evidence of activation of nociceptors related to sympathetic discharge was found, although nociceptors in six CRPS II patients exhibited unrelated spontaneous pathological nerve impulse activity. CONCLUSIONS: We conclude that activation of nociceptors by sympathetic efferent discharges is not a cardinal pathogenic event in either CRPS I or CRPS II patients. SIGNIFICANCE: This study shows that sympathetic-nociceptor interactions, if they exist in patients communicating chronic neuropathic pain, must be the exception.

Label-free 3D optical microangiography imaging of functional vasa nervorum and peripheral microvascular tree in the hind limb of diabetic mice.

Diabetic neuropathy (DN) is, at least in part, associated with the functional attenuation of vasa nervorum, the microvascular structure of peripheral nerves. Microvascular imaging options for vasa nervorum still remain limited. In this work, Optical micro-angiography (OMAG), a volumetric, label-free imaging technique is utilized for characterizing, with high resolution, blood perfusion of peripheral nerve in diabetic mice. We demonstrate that OMAG is able to visualize the structure of microvasculature and to quantify the changes of dynamic blood flow and vessel diameters during administration of vessel stimulator in both diabetic and normal mice. The results indicate the potential of OMAG to assess the blood supply of nerve involved in the pathology and treatment of DN.

Characterization of Tusc5, an adipocyte gene co-expressed in peripheral neurons.

Tumor suppressor candidate 5 (Tusc5, also termed brain endothelial cell derived gene-1 or BEC-1), a CD225 domain-containing, cold-repressed gene identified during brown adipose tissue (BAT) transcriptome analyses was found to be robustly-expressed in mouse white adipose tissue (WAT) and BAT, with similarly high expression in human adipocytes. Tusc5 mRNA was markedly increased from trace levels in pre-adipocytes to significant levels in developing 3T3-L1 adipocytes, coincident with several mature adipocyte markers (phosphoenolpyruvate carboxykinase 1, GLUT4, adipsin, leptin). The Tusc5 transcript levels were increased by the peroxisome proliferator activated receptor-gamma (PPARgamma) agonist GW1929 (1microg/mL, 18h) by >10-fold (pre-adipocytes) to approximately 1.5-fold (mature adipocytes) versus controls (p<0.0001). Taken together, these results suggest an important role for Tusc5 in maturing adipocytes. Intriguingly, we discovered robust co-expression of the gene in peripheral nerves (primary somatosensory neurons). In light of the marked repression of the gene observed after cold exposure, these findings may point to participation of Tusc5 in shared adipose-nervous system functions linking environmental cues, CNS signals, and WAT-BAT physiology. Characterization of such links is important for clarifying the molecular basis for adipocyte proliferation and could have implications for understanding the biology of metabolic disease-related neuropathies.

Pathophysiology of trigeminal neuralgia: new evidence from a trigeminal ganglion intraoperative microneurographic recording. Case report.

The origin of trigeminal neuralgia (TN) appears to be vascular compression of the trigeminal nerve at the root entry zone; however, the physiological mechanism of this disorder remains uncertain. The authors obtained intraoperative microneurographic recordings from trigeminal ganglion neurons in a patient with TN immediately before percutaneous radiofrequency-induced gangliolysis. Their findings are consistent with the idea that the pain of TN is generated, at least in part, by an abnormal discharge within the peripheral nervous system.

Treatment of hemiballismus with stereotactic pallidotomy. Case report and review of the literature.

Hemiballismus is a relatively rare movement disorder that is characterized by uncontrolled, random, large-amplitude movements of the limbs. It is usually caused by a vascular lesion that involves the contralateral subthalamic nucleus (STN) (also known as the nucleus hypothalamicus or corpus luysi) and its afferent and efferent pathways. The authors present a case of medically intractable hemiballismus in a 70-year-old woman who was successfully treated with stereotactic posteroventral pallidotomy. In agreement with the data reported earlier by other groups, the microrecording performed during the pallidotomy showed a decreased rate of firing of the pallidal neurons, supporting the theory of impaired excitatory input from the STN to the internal part of the globus pallidus. Stereotactic pallidotomy may be the procedure of choice in the treatment of medically intractable hemiballismus. Intraoperative microrecording significantly improves the precision of the stereotactic targeting and should be considered a standard part of the pallidotomy protocol.

Background potassium channel block and TRPV1 activation contribute to proton depolarization of sensory neurons from humans with neuropathic pain.

Protons cause a sustained depolarization of human dorsal root ganglion (DRG) neurons [Baumann et al. (1996) Pain, 65, 31-38]. In the present study we sought to determine which ion channels are expressed in human DRG neurons that could mediate the sustained responses observed in the patch-clamp recordings. RT-PCR of material from the DRG tissue revealed the presence of mRNAs for a nonselective cation channel that is activated by protons (TRPV1) and background potassium channels that are blocked by protons (TASK-1, TASK-3 and Kir2.3). Highly acidic solution (pH 5.4) applied to cultured DRG neurons evoked prolonged currents that were associated with a net increase in membrane conductance. Consistent with the involvement of TRPV1, these proton-evoked currents were blocked by capsazepine and were only found in neurons that responded to capsaicin with an increase in membrane conductance. Less acidic extracellular solution (pH 6.0) evoked such currents only rarely, but was able to strongly enhance the currents evoked by capsaicin. Capsazepine (1 microm) blocked the currents evoked by capsaicin at pH 7.35, as well as the potentiated responses to capsaicin at pH 6.0. In neurons that were not excited by capsaicin, moderate extracellular acidification (pH 6.0) caused a sustained decrease in resting membrane conductance. The decrease in membrane conductance by protons was associated with inhibition of background potassium channels. This excitatory effect of protons was not blocked by capsazepine. We conclude that in most neurons the sustained depolarization in response to moderately acidic solutions is the result of blocked background potassium channels. In a subset of neurons, TRPV1 also contributes.

A method for intraoperative microneurographic recording of unitary activity in the trigeminal ganglion of patients with trigeminal neuralgia.

The etiology of trigeminal neuralgia appears to be vascular compression of the nerve at the root entry zone. However, the physiologic mechanism of trigeminal neuralgia remains uncertain. To gain insight into the pathophysiology of the disorder, we developed a method for intraoperative microneurographic recordings from the trigeminal ganglion of patients with trigeminal neuralgia. The recordings are performed immediately prior to standard percutaneous trigeminal gangliolysis for pain relief. Spontaneous or evoked single- and multi-unit action potential activity can be recorded and the location of receptive fields determined. The method should facilitate the testing of hypotheses concerning the origin of this unique pain disorder.

Expression of VPAC2 receptor and PAC1 receptor splice variants in the trigeminal ganglion of the adult rat.

PACAP and VIP are members of the VIP/secretin/glucagon family of peptides with neurotransmitter, neuroprotective, and neurotrophic functions. PACAP and VIP are known to be upregulated in primary sensory neurons following nerve injury, implying that these neuropeptides could be mediators of sensory transmission in neuropathic pain states. Nerve injury at the level of the trigeminal root is thought to be the prime cause of trigeminal neuralgia. Since cross-excitation (a chemically-mediated form of nonsynaptic transmission) within the TG is postulated to play a central role in trigeminal neuralgia, we studied the expression of PACAP and VIP receptors in the TG by RT PCR and immunocytochemistry. Of the three known receptors (PAC1, VPAC1 and VPAC2), RT PCR revealed the presence of mRNA for VPAC2 and several splice variants of the PAC1 receptor. Immunocytochemistry showed PAC1 and VPAC2 to be present in small-diameter TG neurons. Thus, PACAP and VIP are potential mediators of cross-excitation in the TG.

Responses of adult human dorsal root ganglion neurons in culture to capsaicin and low pH.

This study examined the responses of cultured adult human dorsal root ganglion (hDRG) neurons to protons and capsaicin, two substances known to produce pain and hyperalgesia in humans. Both substances were applied to each neuron and responses were examined under both voltage- and current-clamp recording conditions. Sensitivity to protons was tested with rapid acidification of the extracellular fluid from pH 7.35 to 6.0. In neurons nominally clamped near -60 mV, low pH evoked a transient inward current which, in all 40 hDRG neurons tested, was followed by a more sustained inward current. The sustained current was associated with an increase in membrane conductance in 10 neurons, a decrease in 27 neurons, and no overt change in conductance (< 10%) in 3 neurons. Current-clamp recordings in the same neurons showed that the proton-induced sustained net inward current caused a prolonged depolarization of the membrane potential in all 40 hDRG neurons. The prolonged depolarization was associated with action potential discharge in 5 neurons. Unlike low pH, capsaicin evoked a sustained net inward current in only a subset of neurons tested (10 nM: 1/4, 30 nM: 4/8, 100 nM: 11/18, and 10 microM: 10/10 neurons tested). The capsaicin-evoked currents were accompanied by an increase in membrane conductance in 15 neurons, a decrease in 2, and no overt change in conductance in 9 neurons. Capsaicin currents, like proton-induced currents, resulted in prolonged depolarizations (10 nM: 0/4, 30 nM: 5/8, 100 nM: 8/18, and 10 microM: 10/10 neurons tested). The depolarization resulted in the discharge of action potentials in 14 neurons. It is concluded that, while both protons and capsaicin exert excitatory effects on human sensory neurons, multiple membrane mechanisms lead to the depolarization of cultured hDRG neurons by low pH. Inhibition of resting membrane conductances contributes to the responses to low pH in some hDRG neurons.

Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin.

Psychophysical measurements of pain and mechanical hyperalgesia were obtained following different doses of capsaicin injected intradermally into the forearms of human subjects. Each subject received a 10 microliter injection of the vehicle and capsaicin doses of 0.01, 0.1, 1, 10 and 100 micrograms. The relationship between capsaicin dose and the magnitude and duration of pain was determined using the method of magnitude estimation. In addition to pain, capsaicin produced a flare and mechanical hyperalgesia. The area of flare and the area and time course of mechanical hyperalgesia were measured as a function of the dose of capsaicin. The magnitude and duration of pain, based on averaged responses of all subjects, increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce more pain than the vehicle was 0.1 micrograms. The area and duration of mechanical hyperalgesia also increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce an area of mechanical hyperalgesia was 0.1 micrograms. An area of hyperalgesia was present within seconds following injection. For doses of 10 and 100 micrograms, the area of hyperalgesia grew to reach a maximum within 5 and 7 min following the injection and gradually decreased, disappearing within 15 and 137 min, respectively. Capsaicin doses of 1, 10 and 100 micrograms produced successively greater areas of flare. The results demonstrate that humans can scale the magnitude of pain produced by capsaicin in a dose-dependent fashion. Further, the duration of pain, the area and duration of mechanical hyperalgesia, and the area of flare are dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)