Application of local anesthesia inhibits effects of low-energy extracorporeal shock wave treatment (ESWT) on nociceptors.

OBJECTIVE: Clinical studies of extracorporeal shock wave therapy (ESWT) provided conflicting results depending on the use of local anesthesia (LA). DESIGN: The present study investigated whether the biological effects of ESWT differ between application with and without LA. SETTING AND PATIENTS: In 20 healthy subjects, ESWT was applied to the ventral surface of forearm skin, either after topical lidocaine pretreatment or without on the corresponding contralateral side. MEASURES: During and after ESWT ongoing pain, axon-reflex vasodilation (laser Doppler imaging), thresholds for pinprick, and blunt pressure were recorded. RESULTS: The results indicate that increasing ESWT energy flux density led to increasing pain (P < 0.001). LA reduced ESWT-related pain (P < 0.02) and in parallel inhibited local axon-reflex vasodilation (P < 0.001). In addition, LA prevented ESWT-related drop in pressure pain threshold (P < 0.001). CONCLUSION: This study provided evidence that ESWT dose-dependently activates and sensitizes primary afferent nociceptive C-fibers, and that both activation and sensitization were prevented if LA was applied locally. These results suggest that LA substantially alters the biological responses of ESWT.

The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism.

Using the C-fibre reflex as a nociceptive response elicited by a wide range of stimulus intensities in the rat, we recently reported that a single treatment with (+)-HA966, a glycine site-specific NMDA receptor antagonist: (1) potentiates morphine antinociception; and (2) reverses an established morphine tolerance. We presently aimed at determining whether our observation was likely to result from a direct effect on the spinal cord or an indirect effect of supraspinal origin. In a 2x2x2 experimental design, we compared the effects of 5 mg/kg morphine in: (1) sham-operated rats or animals whose brainstems had been transected at the level of the obex; (2) rats that were implanted with pellets, either 150 mg morphine or placebo; and (3) animals injected either with saline or 10 mg/kg (+)-HA966. The control C-fibre reflexes were similar in all groups of animals. As compared to "non-tolerant" rats, the depressive effect of morphine was weaker in "morphine-tolerant" animals where the threshold did not change following morphine but the gain of the stimulus-response curve decreased, albeit to a significantly lesser extent than in the "non-tolerant" group. Whether in "non-tolerant" or "tolerant" groups, the effects of morphine were stronger in "obex-transected" than in "sham-operated" animals. In all groups, the effects of morphine were potentiated by the preliminary administration of (+)-HA966. However, in the "morphine-tolerant" group, the preliminary administration of (+)-HA966 was more potent in the "sham-operated" than in the "obex-transected" groups. Since overall effects were very similar in "sham-operated" and "obex-transected" animals, we concluded for our model that the critical site for the expression of the neuronal plastic changes associated with morphine tolerance lies in the spinal cord.

Laser evoked potentials in patients with trigeminal disease: the absence of Adelta potentials does not unmask C-fibre potentials.

OBJECTIVE: Although laser stimuli activate both Adelta- and C-fibres, the corresponding laser evoked potentials (LEPs) remain restricted to the Adelta-fibre input. Previous studies found C-LEPs after limb stimulation only in subjects with block or clinical impairment of Adelta-fibres. In this study, we aimed at verifying whether in the trigeminal territory the impairment of Adelta-fibres unmasks the C-LEP. METHODS: By collecting retrospectively LEPs recorded in 370 patients, we analyzed the results from 150 trigeminal divisions with absent Adelta-LEPs. RESULTS: We found signals that were consistent with the C-fibre input in three patients only. In most patients with absent Adelta-LEPs, however, laser stimuli still elicited the Adelta-conveyed pinprick sensation. CONCLUSIONS: The preserved pinprick sensation suggests that the Adelta-fibre volley, though weakened, reached the cortex. The C-LEP absence may be explained according to the first come first served hypothesis: the evoked potential related to an afferent volley reaching the cortex shortly after a preceding input (i.e. a C-fibre volley coming after an Adelta-fibre) will be suppressed. SIGNIFICANCE: In clinical studies using the standard laser pulses to evoke the Adelta-LEPs, the finding of absent signals does not indicate a concomitant impairment of C-fibres.

Paracrine-like excitation of low-threshold mechanoceptive C-fibers innervating rat hairy skin is mediated by substance P via NK-1 receptors.

We reported previously that C-fibers innervating rat skin can be excited by short trains of electrical shocks ('tetanus') applied to neighboring nerves. Since these nerves were disconnected from the CNS, the cross-talk is located peripherally. Here we tested if low-threshold mechanoceptive (LTM) C-fibers can be excited by this cross-talk and if this process is mediated by substance P (SP) via neurokinin-1 (NK-1) receptors. In urethane anesthetized rats we found that 80% (56/71) of LTM C-fibers, recorded in the lateral cutaneous branch of the dorsal ramus (CBDR) of T10 spinal nerve, were excited by a 10s, 20 Hz tetanus of the T9 CBDR. Compared to the spontaneous pre-tetanic firing frequency of 1.62+/-0.40 impulses/30s, the frequency significantly increased to 3.74+/-0.99, 3.17+/-0.69 and 2.92+/-0.63 impulses/30s, at 30, 60 and 90 s after the tetanus, respectively, and declined to the baseline frequency thereafter. When injected into their receptive fields, SP mimicked the tetanically induced increase of firing rate, whereas the NK-1 receptor antagonist WIN 51708 blocked the excitation in most fibers. The excitation was significantly diminished in adult rats that were neonatally treated with capsaicin, a treatment that destroys most SP-expressing afferent fibers. Thus, we conclude that peptidergic primary afferents are functionally linked with adjacent LTM C-fibers in a non-synaptic, paracrine-like signaling pathway via SP and NK-1 receptors, and perhaps also other agents as well. We propose that this cross-talk has evolved as a mechanism regulating the mechanoceptive characteristics of LTM C-fibers, presumably contributing to pain sensation elicited by tactile stimuli ('allodynia').

Involvement of peripheral ionotropic glutamate receptors in activation of cutaneous branches of spinal dorsal rami following antidromic electrical stimulation of adjacent afferent nerves in rats.

The aim of the present study was to investigate the role of peripheral ionotropic glutamate receptors in the process of signal transmission between adjacent different peripheral sensory nerves. The T9 and T10 cutaneous branches of spinal dorsal rami were dissociated and cut proximally in pentobarbital anesthetized rats. Eighty-seven single afferents from T10 nerve filaments were recorded and characterized by assessing their spontaneous activities. Following 30 s antidromic electrical stimulation (intensity: 1 mA; duration: 0.5 ms; frequency: 20 Hz) of T9 cutaneous branches, the spontaneous activities of Abeta, Adelta and C fibers of T10 nerve were significantly enhanced from 2.00+/-0.34, 2.42+/-0.33, and 2.19+/-0.32 impulses/min to 4.31+/-0.58, 5.22+/-0.55, and 5.27+/-0.69 impulses/min, respectively (n=29 for each type, P<0.05). These enhanced spontaneous discharges of T10 nerve were significantly blocked by local treatment of its receptive field with either N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 or non-NMDA receptor antagonist DNQX (0.1 mM, 10 microl for each drug) (P<0.05). These results suggest that peripheral ionotropic glutamate receptors are involved in the activation of peripheral nerves following the antidromic stimulation of adjacent afferents from different spinal segments. We further provide the direct evidence that neurotransmitters released from adjacent peripheral nerves may also contribute to the occurrence of allodynia as well as secondary hyperalgesia during the pathological nociception.

Sensitization and habituation of AMH and C-fiber related percepts of repetitive radiant heat stimulation.

OBJECTIVE: Pain perception involves neuronal plasticity at peripheral and central stages, resulting in sensitization or habituation, depending on intensity and temporal features of stimulation. Concurrent assessment of perceptual change over different time spans is therefore important for understanding the dynamics of pain processing. METHODS: A new psychophysical procedure was established to assess sensitization and habituation during repetitive radiant heat stimulation. Short-term perceptual change (<1 min) during trials with 10 stimuli applied at 3 frequencies (0.2-0.6-1.8 Hz) and 3 intensities was assessed for AMH-II or C-fiber related percepts. Perceptual changes were monitored for medium-term (1-15 min) and for long-term (15-90 min) time spans. RESULTS: Short-term sensitization occurred only at frequencies above 0.3 Hz and was affected by both stimulus frequency and intensity, but the AMH-fiber related sensitization depended on intensity only above 0.6 Hz. Multiple stimulation of the same skin area during medium-term time spans resulted in habituation. No long-term perceptual changes occurred. CONCLUSIONS: The procedure permits concurrent assessment of short-term sensitization and medium-term habituation, assumed to be related to spinal windup and cutaneous nociceptive fiber fatigue, respectively. SIGNIFICANCE: The method is suitable for quantitative sensory testing of dynamic pain processing over different time spans, relevant in clinical testing of pain and in drug assessment.

Involvement of nitric oxide in long-term potentiation of spinal nociceptive responses in rats.

Nitric oxide plays an important role in spinal nociception. The present study explored the effects of nitric oxide on the spinal long-term potentiation associated with nociception. (1) Nitric oxide synthase inhibitor L-NAME (1 mM, 20 microl) and the nitric oxide scavenger hemoglobin (2 mg/ml, 20 mul) strikingly blocked the induction of tetanic sciatic stimulation-induced spinal long-term potentiation of C-fiber-evoked field potentials. L-arginine, a substrate of nitric oxide synthase, completely reversed L-NAME-induced inhibition. However, D-NAME (1 mM, 20 microl), an inactive form of L-NAME, had little effect on the spinal LTP. (2) The same tetanic sciatic stimulation induced long-term thermal hyperalgesia, which was blocked by pre-application of L-NAME. These results suggest the involvement of nitric oxide in the spinal long-term potentiation of C-fiber-evoked field potentials and related behavior changes.

Differential activation of trigeminal C or Adelta nociceptors by infrared diode laser in rats: behavioral evidence.

Radiant heat is often used for studying thermal nociception, although inherent characteristics such as the broad spectrum of applied wavelengths of typical light sources limit control over and repeatability of stimuli. To overcome these problems, we used a diode infrared laser-based stimulator (wavelength: 980 nm) for selectively stimulating trigeminal Adelta or C thermonociceptors in rats. To provide indirect evidence for nociceptor-selective stimulation, we tested the effects of capsaicin, dimethylsulfoxide (DMSO), and morphine on withdrawal latencies for long pulses with a low current (hypothesized to selectively stimulate C nociceptors) and for threshold currents of short pulses with high current (hypothesized to selectively stimulate Adelta nociceptors) in lightly anesthetized rats. Nonmem analysis was used to perform pharmacodynamic modeling. The measured baseline withdrawal latency for long pulses was 12.5 +/- 0.3 s which was changed significantly to 6.7 +/- 0.4 s after applying topical capsaicin which selectively sensitizes C nociceptors and to 16.5 +/- 1.3 s after 1.0 mg/kg morphine which preferentially attenuates C fiber nociception. Topical DMSO which appears to selectively sensitize Adelta afferents did not significantly alter withdrawal latencies to the long pulses. Fitted threshold currents for short pulses after DMSO were however significantly lower (974 +/- 53 mA vs. 1113 +/- 12 mA for baseline) indicating Adelta sensitization. Capsaicin and morphine did not significantly change threshold currents. Best Nonmem fits for the long pulse were obtained using a model assuming no DMSO effect, but a different inter-individual variability after applying this substance. For the short pulse, a model assuming no capsaicin or morphine effect, but again allowing different inter-individual variabilities after applying these drugs, best described the data. We conclude that different settings of the stimulator used in this study were capable of selectively activating trigeminal Adelta or C thermonociceptors.

Innocuous skin cooling modulates perception and neurophysiological correlates of brief CO2 laser stimuli in humans.

The present study examined the influence of innocuous skin cooling on the perception and neurophysiological correlates of brief noxious CO2 laser stimuli. In nine normal subjects, brief CO2 laser pulses of four different intensities (duration 50 ms; diameter 5 mm; intensity range 5.8-10.6 mJ/mm2) were delivered at random every 5-10 s on the dorsum of the hand. Innocuous skin cooling was performed by a thermode (20 degrees C; 3x3 cm) with a central hole for the laser test stimuli. Quality and intensity (VAS) of perceptions, reaction times and laser evoked potentials (LEPs) were examined. Signal detection theory analysis was performed to evaluate discrimination performance and decision criterion. During innocuous skin cooling, detection threshold increased from 4.8+/-1.81 to 8.2+/-1.05 mJ/mm2 and pain threshold from 8.7+/-1.53 to 13.5+/-1.57 mJ/mm2. proportion of detected stimuli decreased from 87% to 48% and pain reports from 42% to 10%. The well localized 'pricking' sensation mediated by Adelta-nociceptors almost vanished. The intensity of sensations (VAS scores) was considerably reduced. Sensory discriminative performance was significantly depressed but decision criterion remained unchanged. Reaction times were delayed. The late-LEPs, correlates of Adelta-nociceptor activations, were also significantly depressed while the ultra-late LEPs, correlates of C-nociceptors, were not affected. Taken together, these results strongly suggest that innocuous skin cooling interfered with the sensory processing of laser heat stimuli and more prominently with those related to Adelta-nociceptive input.

Role of unmyelinated fibers in electroacupuncture cardiovascular responses.

The afferent fiber type responsible for the transmission of sensory neural traffic to the central nervous system during acupoint stimulation is uncertain. Several early studies evaluating compound action potentials have suggested that myelinated fibers contribute to the afferent input of the autonomic reflex adjustments during electroacupuncture (EA). Our more recent data, employing single unit recordings of somatic afferents, show that both myelinated and unmyelinated fibers are stimulated by EA, although more finely myelinated than unmyelinated fibers are activated by low frequency, low current stimulation. We hypothesized in this study that unmyelinated group VI fibers also contribute significantly to the inhibitory influence of EA on cardiovascular pressor responses. We found that neonatal capsaicin-treated rats depleted of substance P from primary afferents were insensitive to the inhibitory EA effect during gastric distention. Thus, EA at P5-P6 reduced gastric distention-induced pressor responses from 19+/-3 to 11+/-2 mmHg in eight untreated rats while capsaicin-treated rats (n=9) were unresponsive to EA. Substance P containing neurons in dorsal root ganglion cells at Ti-T5 were significantly decreased in the capsaicin-treated rats from 47+/-4 to 22+/-4 cells. Treated compared to untreated rats also demonstrated a significantly (P<0.03) reduced number of group IV fibers identified with single unit recording techniques. This study demonstrates that the inhibitory effect of EA at P5-P6 on cardiovascular autonomic excitatory reflexes involves unmyelinated group IV fibers of the median nerves.

Stimulation of PAR-2 excites and sensitizes rat cutaneous C-nociceptors to heat.

Proteinase-activated receptor 2 (PAR-2) is expressed on many nociceptive neurons. Application of PAR-2 agonists has been shown to induce behavioral signs of hyperalgesia. We investigated effects of the rat PAR-2 agonist SLIGRL-NH2 in the isolated rat skin-saphenous nerve preparation. SLIGRL-NH2 (100 microM) excited 20% of all C-fiber nociceptors tested. In addition, C-fiber nociceptors were sensitized to heat after SLIGRL-NH2 application resulting in an increase in response magnitude and a decrease of heat threshold. The PAR-2-inactive control peptide LRGILS-NH2 had no effect. The mechanical sensitivity of C-fibers was not affected by SLIGRL-NH2. PAR-2-mediated excitation and sensitization of primary nociceptors may contribute to PAR-2-mediated hyperalgesia.

A reliable method for the preferential activation of C- or A-fibre heat nociceptors.

There is strong evidence that A- and C-fibre nociceptors evoke significantly different sensory experiences, are differentially sensitive to pharmacological intervention, and play different roles in pain pathology. It is therefore of considerable interest to be able to selectively activate one fibre type or the other in studies of nociceptive processing. Here, we report significant modifications to a non-invasive technique, first described by Yeomans et al. [Pain 59 (1994) 85; Pain 68 (1996) 141; Pain 68 (1996) 133], which uses different rates of skin heating to preferentially activate A- or C-nociceptors. A copper disk (diameter: 4mm) was used to transfer heat evenly across the dorsal surface of the rat hindpaw. Initial experiments established the relationship between the temperature at the skin surface and the sub-epidermal temperature. Subsequently, the vanilloid capsaicin, which sensitises unmyelinated C-mechanoheat nociceptors, was shown to decrease the thresholds of reflex responses evoked by slow rates of heating. In contrast thresholds of responses to fast rates of skin heating were unchanged, indicating that nociceptors activated by this stimulus were capsaicin-insensitive A-fibre heat nociceptors.

Microneurographic study of C fiber discharges induced by CO2 laser stimulation in humans.

We investigated C-fiber discharges and cerebral potentials evoked by weak CO(2) laser beams applied to a tiny skin area in five healthy subjects. Microneurography was performed from the peroneal nerve in the right popliteal area. Cerebral potentials were recorded from the Cz electrode referred to linked earlobes. The mean conduction velocity of five stable single units was 1.1+/-0.3 m/s. The mean latency of the positive peak of cerebral potentials was 1327.4+/-46.2 ms. These findings indicated that this new stimulation method selectively activated C-fiber nociceptors of the skin.

Laser evoked potentials for assessing sensory neuropathy in human patients.

Sensory neuropathy usually impairs tactile sensations related to large myelinated afferents (Abeta) as well as thermal-pain sense related to small myelinated (Adelta) and unmyelinated (C) afferents. By selectively affecting large or small fibres, some sensory neuropathies may also provoke a dissociated sensory loss. Standard nerve conduction studies and somatosensory evoked potentials assess Abeta-fibre function only. Laser pulses selectively excite free nerve endings in the superficial skin layers and evoke Adelta-related brain potentials (LEPs). From earlier studies and new cases we collected data on 270 patients with sensory neuropathy. LEPs often disclosed subclinical dysfunction of Adelta fibres and proved a sensitive and reliable diagnostic tool for assessing small-fibre function in sensory neuropathy.

Single-trial detection of human brain responses evoked by laser activation of Adelta-nociceptors using the wavelet transform of EEG epochs.

The aim of this study was to identify EEG changes induced by Adelta-nociceptor activation in single trials. In a preliminary experiment, intense CO(2) laser stimuli were delivered to the hand dorsum of five volunteers. The average amplitude of EEG epochs was estimated in the time-frequency (TF) domain using the continuous Morlet wavelet transform (CMT). The result was used as a TF filter enhancing Adelta-nociceptor induced EEG responses. In a second experiment, eight other subjects were delivered laser stimuli with six intensities. The CMT of each EEG epoch was computed. After applying the TF filter, amplitudes within a predefined interval were summed. Whether this sum predicted the occurrence of Adelta-nociceptor activation was tested using the reaction-time to discriminate between Adelta- or C-fibre mediated detection. Results showed that this method accurately identified single-trial EEG responses to Adelta-nociceptor activation.

Supraspinal and systemic administration of the nicotinic-cholinergic agonist (+/-)-epibatidine has inhibitory effects on C-fiber reflexes in the rat.

This study assessed the effects of the nicotinic agonist (+/-)-epibatidine (EPIB) on the C-fiber flexor reflex in the anesthetized rat. Electrical stimulation of the hindpaw produces a long latency (> 150 ms) C-fiber mediated electromyographic (EMG) burst in hindlimb flexor muscles. EPIB (0.01, 0.03 micromol/kg, i.p.) significantly reduced (p < 0.05) C-fiber -related EMG activity by 46 and 64%, respectively. This effect was similar to that produced by the opioid morphine (21.0 micromol/kg, i.p.) and the NMDA receptor antagonist MK-801 (3.0 micromol/kg, i.p.). Nicotinic receptor blockade with the antagonists mecamylamine (5.0 micromol/kg, i.p.) and chlorisondamine (23.0 nmol/rat, intracerebroventricular) attenuated the effects of systemic EPIB on the C-fiber reflex. EPIB injection (0.04 nmol/rat) into the nucleus raphe magnus significantly decreased C-fiber EMG activity by 67%, suggesting a supraspinal site of action. In contrast, EPIB (0.6 nmol/rat) administered into the lumbar spinal cord significantly increased the C-fiber reflex by 117%. In summary, systemic and supraspinal EPIB exerted an inhibitory effect on central pain transmitting pathways, while a stimulatory effect is elicited in the spinal cord. The inhibitory effects are consistent with the reported analgesic properties of EPIB. The excitatory effect may be related to the reported algogenic responses when EPIB is administered intrathecally.

Rigorous Green's function formulation for transmembrane potential induced along a 3-D infinite cylindrical cell.

The quasi-static electromagnetic field interaction with three-dimensional infinite-cylindrical cell is investigated for both intracellular (IPS) and extracellular (EPS) current point-source excitation. The induced transmembrane potential (TMP), expressed conventionally via Green's function, may alternatively be expanded into a faster-converging representation using a complex contour integration, consisting of an infinite-discrete set of exponentially decaying oscillating modes (corresponding to complex eigenvalues) and a continuous source-mode convolution integral. The dominant contributions for both the IPS and EPS problems are obtained in simple closed-form expressions, including well documented special mathematical functions. In the IPS case, the dominant modal contribution (of order zero)--an exact solution of the well-known cable equation--is explicitly and analytically corrected by the imaginary part of its eigenvalue and the source-mode convolution contribution. However, the TMP along a fiber was shown to decay at infinity algebraically and not exponentially, as predicted by the classic cable equation solution. In the EPS case, the dominant contribution is expressed as a source-mode convolution integral. However, for a long EPS distance (e.g., >10 cable length constant) the order-one-modes involved in the convolution is not a solution of the cable equation. Only for shorter EPS distance should the cable equation solution (i.e., the order zero dominant mode) be included in addition to the modes of order one. For on-membrane EPS location, additional modes should be included as well. In view of our EPS result, we suggest that the cable equation modeling existing in the literature and related to functional electrical stimulation for EPS problems, should be critically reviewed and corrected.

How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation.

This review presents and discusses the leading arguments justifying the use of high power laser stimulators to explore the nociceptive system. To grasp the particularity of such stimulators, fundamentals concerning the interaction of low-energy radiation with the skin will be recalled and focused on the optimal match between the wavelength of the emitting source and the thermophysical properties of the skin. This knowledge shall allow us to discuss critical characteristics of laser stimulators. Study of the cutaneous spectrum of receptors showed that laser stimulators allow the selective activation of A(delta) and C-fiber nociceptors. We will present different methods, which increase the selectivity of the laser stimulation, restricting the activation to isolated C-fiber nociceptors. These methods open new perspectives in the study of the cerebral processing of signals ascending through A(delta) and/or C nociceptors and should contribute to a better understanding of their central interaction and integration in normal and pathological states.

Thermal detection thresholds of Aδ- and C-fibre afferents activated by brief CO2 laser pulses applied onto the human hairy skin.

Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO(2) laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.

Differential processing of laser stimuli by Aδ and C fibres in major depression.

Clinical studies have revealed that up to 92% of major depressed patients report pain complaints such as back or abdominal pain. Furthermore, patients suffering from depression exhibit increased superficial pain thresholds and decreased ischemic (deep) pain thresholds during experimental pain testing in comparison to healthy controls. Here, we aimed to investigate a putative role of Aδ- and C-fibre activation in altered pain perception in the disease. Laser-evoked potentials (LEPs) of 27 unmedicated depressed patients and 27 matched controls were recorded. Aδ and C fibres were activated separately. Amplitudes and latencies of N2 and P2 peaks of Aδ- (Aδ-LEP) and C-fibre- (C-LEP) related LEPs were evaluated. Depressed patients showed significantly decreased Aδ-LEP amplitudes (N2 peak: P=0.019; P2 peak: P=0.024) and delayed C-LEP latencies (P2 peak: P=0.0495; N2 peak: P=0.0556). In contrast, C-LEP amplitudes and Aδ-LEP latencies were unaffected. Our results might be suggestive of the differential impact of physiological changes on pain processing in depression. Thus, Aδ-LEP might reflect the physiological correlate of the augmented superficial pain thresholds during depression. On the contrary, the C-fibre component mediates the facets of pain processing, outlasting the stimulation period, and has been shown to be exaggerated in chronic pain states. Therefore, the functional over-representation of the C-fibre component found in our study might be a possible link between depression and associated pain complaints.