[Diagnosis of neuropathic pain]. / Diagnostik neuropathischer Schmerzen.

Pain usually is the consequence of tissue damage that is signalled to the brain via the nociceptive system (nociceptive pain). Damage to the nociceptive system - in addition to causing sensory deficit - may paradoxically also induce a chronic pain state (neuropathic pain). Diagnostic workup of patients with neuropathic pain follows the usual procedure of Neurology, i. e. the aim is to identify the location of neural damage and the underlying disorder, so that a mechanism-oriented treatment may be initiated. Medical history - supported by specific questionnaires and a pain drawing by the patient - provides the basis for diagnosis. In the course of the physical examination, the sensory exam including careful documentation of the spatial extent of positive and negative signs is the most important part, since neuropathic pain is due to damage to the somatosensory system. Techniques for the objective documentation of sensory signs have been developed (e. g. by the DFNS), but their broad availability is still in teh process of being implemented. Thus, laboratory exams main serve the purpose of identifying the underlying etiology. Symptomatic treatment of neuropathic pain is relatively uniform, independent of etiologies (e. g. traumatic, metabolic, inflammatory), but differs from that of nociceptive pain. Typical analgesics have little efficacy in neuropathic pain - except for opioids. Major pharmacological treatment options include anticonvulsants (Ca-channel modulators, Na-channel blockers), antidepressants (noradrenaline reuptake inhibitors) and topicals (lidocaine, capsaicin). These medications exert specific molecular pharmacological effects against the pathophysiological mechanisms of neuropathic pain.

Characterization of three different sensory fibers by use of neonatal capsaicin treatment, spinal antagonism and a novel electrical stimulation-induced paw flexion test.

In the present study, we first report an in vivo characterization of flexor responses induced by three distinct sine-wave stimuli in the electrical stimulation-induced paw flexion (EPF) test in mice. The fixed sine-wave electric stimulations of 5 Hz (C-fiber), 250 Hz (Adelta-fiber) and 2000 Hz (Abeta-fiber) to the hind paw of mice induced a paw-flexion response and vocalization. The average threshold for paw flexor responses by sine-wave stimulations was much lower than that for vocalization. Neonatally (P3) pretreatment with capsaicin to degenerate polymodal substance P-ergic C-fiber neurons increased the threshold to 5 Hz (C-fiber) stimuli, but not to 250 Hz (Adelta-fiber) and 2000 Hz (Abeta-fiber). The flexor responses to 5 Hz stimuli were significantly blocked by intrathecal (i.t.) pretreatment with both CP-99994 and MK-801, an NK1 and NMDA receptor antagonist, respectively, but not by CNQX, an AMPA/kainate receptor antagonist. On the other hand, the flexor responses induced by 250 Hz stimuli were blocked by MK-801 (i.t.) but not by CP-99994 or CNQX. In contrast, flexor responses induced by 2000 Hz stimuli were only blocked by CNQX treatment. These data suggest that we have identified three pharmacologically different categories of responses mediated through different primary afferent fibers. Furthermore, we also carried out characterization of the in vivo functional sensitivity of each of the sensory fiber types in nerve-injured mice using the EPF test, and found that the threshold to both 250 Hz and 2000 Hz stimulations were markedly decreased, whereas the threshold to 5 Hz stimulations was significantly increased. Thus we found opposing effects on specific sensory fiber-mediated responses as a result of nerve injury in mice. These results also suggest that the EPF analysis is useful for the evaluation of plasticity in sensory functions in animal disease models.

Effect of ionotropic glutamate receptor antagonists on Fos-like immunoreactivity in the dorsal horn following transection of the rat sciatic nerve.

Fos-like immunoreactivity (FLI) was investigated in the lumbar dorsal horn 2 h after transection of the rat sciatic nerve and sham operation. FLI following nerve transection was distributed through the medio-lateral extension of the superficial layer of the dorsal horn, while FLI after sham operation, tissue injury, was restricted to the lateral one-third of this layer. The number of FLI neurons in the lateral one-third was similar in the two operations, indicating that neurons expressing FLI in the medial two-thirds and in the lateral one-third of the superficial layer after nerve transection are derived from nerve injury and tissue injury, respectively. FLI in the lateral one-third, but not the medial two-thirds, after nerve transection was significantly reduced by pretreatment with NMDA and AMPA/KA receptor antagonists, indicating that there is a considerable difference in the contributions of ionotropic glutamate receptors to FLI in this layer induced by nerve injury and tissue injury.

Peripheral nerve injury leads to the establishment of a novel pattern of sympathetic fibre innervation in the rat skin.

Peripheral nerve injury has been shown to result in sympathetic fibre sprouting around dorsal root ganglia (DRG) neurons. It has been suggested that this anomalous sympathetic fibre innervation of the DRG plays a role in neuropathic pain. Other studies have suggested an interaction between sympathetic and sensory fibres more peripherally. To date, no anatomical study of these possible interactions in the terminal fields of sensory and sympathetic fibres has been performed; therefore, the authors set out to study them in the rat lower lip after bilateral lesions of a sensory nerve, the mental nerve (MN). Immunocytochemistry for both substance P (SP) and dopamine-beta-hydroxylase (DbetaH) was performed. Within the first week post-MN lesions, the SP-immunoreactive (IR) fibres had degenerated almost completely, whereas DbetaH-IR fibres were found in the upper dermis, an area from which they normally are absent. These DbetaH-IR fibres were present in the upper dermis at all postsurgery times studied (1, 2, 3, 4, 6, and 8 weeks). It is noteworthy that, although, by week 6 post-MN lesions, SP-IR fibre reinnervation of the lower lip was occurring, the DbetaH-IR fibres still were present in the upper dermis. Quantification revealed that the migration and branching of the DbetaH-IR fibres into the upper dermis occurred gradually and was most significant at 4 weeks post-MN lesions, as demonstrated by the fact that the DbetaH-IR fibres were found 169.6 +/- 91.4 microm away from the surface of the skin compared with 407.1 +/- 78.4 microm away in sham-operated animals. These findings suggest that the ectopic innervation of the upper dermis by sympathetic fibres may be important in the genesis of neuropathic pain through the interactions of sympathetic and SP-containing sensory fibres.

[Characteristics of the innervation of the head and neck]. / Besonderheiten der Innervation des Kopf-Hals-Bereichs.

Innervation of the head and neck differs from other regions of the body in certain respects. In particular, besides the external cuneate nucleus, thick-calibre neck muscle afferents project directly, to the vestibular nuclear complex. This projection is most prominent in segments C2 and 3 and is sparse or absent in more caudal segments. Thus, proprioceptive neck muscle afferents gain direct access to vestibulospinal, vestibulooculomotor and other secondary or even higher order vestibular neurons that receive labyrinthine input. Proprioceptive input via indirect spinovestibular pathways is also most prominent from C2 and 3 compared to more caudal levels. Likewise, thin calibre, mainly nociceptive afferents from cervical segments are channelled via the parabrachial nuclei in the rostral pons to limbic structures different from the targets of thoracolumbar afferents. It is tempting to consider these neuroantomical peculiarities relevant for the pathogenesis of the puzzling symptoms after whiplash injury.

Responses to heat of C-fiber nociceptors in monkey are altered by injury in the receptive field but not by adjacent injury.

We sought to determine the effects of a cut injury on the thermal responsiveness of C-fiber nociceptors sensitive to heat and mechanical stimuli (CMHs). Teased fiber techniques were used to record from single CMHs that innervated the hairy skin of the monkey arm. Responses to heat stimuli ranging from 41 to 49 degrees C were compared before and after injury. In 11 CMHs, the injury was applied 4 mm peripheral to the edge of the receptive field. The response to the heat sequence was not significantly altered by this adjacent injury. In 16 CMHs, a cut was applied directly to the receptive field. This direct injury led to a significant increase in response to the sequence of heat stimuli (i.e., sensitization). It is concluded that spreading sensitization of C-fiber nociceptors to a cut injury does not occur in monkey.