Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

BACKGROUND: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. METHODS: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. RESULTS: While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. CONCLUSIONS: These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. SIGNIFICANCE: S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.

Central nervous system networks involved in the processing of meningeal and cutaneous inputs from the ophthalmic branch of the trigeminal nerve in the rat.

This study analysed the organization of central nervous system networks involved in the processing of meningeal inputs in the male, Sprague-Dawley rat. We injected the anterograde tracer, biotin dextran, into areas of the medullary trigeminal nucleus caudalis (Sp5C), which receive inputs from the ophthalmic division of the trigeminal nerve. Double-labelling immunohistochemical studies were then performed to compare calcitonin gene-related peptide (CGRP) or serotonin 1D (5HT1(D)) receptor distributions in the areas innervated by Sp5C neurons. Dense, topographically organized intratrigeminal connections were observed. Sp5C neurons projected to the commissural subnucleus of the solitary tract, A5 cell group region/superior salivatory nucleus, lateral periaqueductal grey matter, inferior colliculus and parabrachial nuclei. Trigeminothalamic afferents were restricted to the posterior group and ventroposteromedial thalamic nuclei. Some of these areas are also immunoreactive for 5HT1(D) and CGRP and thus remain potential central targets of triptan molecules and other antimigraine drugs.

Nociceptive stimulation activates locus coeruleus neurones projecting to the somatosensory thalamus in the rat.

In the thalamus, noradrenergic output from the pontine nucleus locus coeruleus (LC) may actively shape the response properties of various sensory networks en route to the cortex. Little is known, however, about the involvement of ascending noradrenergic innervation of the somatosensory thalamus in the processing of nociceptive information. To address this question, we combined the study of Fos expression upon nociceptive tooth pulp stimulation in the anaesthetized rat, with the detection of retrogradely traced neurones from the somatosensory thalamus. Cell bodies labelled retrogradely from the left thalamus were observed on both sides of the LC, with an ipsilateral predominance (n = 8). Electrical stimulation of the right incisor pulp (n = 4) provoked a significantly stronger Fos expression (around twice) than sham surgery (n = 4), in both the ipsi- and contralateral LC. Significantly larger numbers of double labelled neurones were counted in the LC of tooth-pulp-stimulated animals (representing around 30% of retrogradely labelled cells in LC) than in the LC of sham animals. They were found bilaterally, but with a clear, significant, ipsilateral (i.e. left) predominance. The present data offer an anatomical framework to understand how the LC is involved in the sensory processing of nociceptive information in the thalamus. For the first time, it is shown that nociceptive stimulation activates LC neurones projecting to the somatosensory thalamus. This suggests a new role for LC in modulating nociception within the thalamus.

Ascending connections from the caudal part to the oral part of the spinal trigeminal nucleus in the rat.

The brainstem trigeminal somatosensory complex, while sharing many common aspects with the spinal somatosensory system, displays features specific to orofacial information processing. One of those is the redundant representation of peripheral structures within the various subnuclei of the complex. A functional redundancy also exists since a single sensory modality, e.g. nociception, may be processed within different subnuclei. In the present study, we addressed the question whether anatomical connections from the caudal part to the oral part of the spinal trigeminal nucleus may support topographical and functional redundancy within the rat trigeminal somatosensory complex. The retrograde tracer tetramethylrhodamine-dextran was injected iontophoretically into the oral subnucleus of anaesthetised rats. Cell bodies labelled retrogradely from the oral subnucleus were observed in laminae III-IV and V of the ipsilateral caudal subnucleus consistently, and to a lesser degree in lamina I. Such a distribution of retrogradely labelled cells suggested that specific subsets of neurones may relay nociceptive information, and others non-nociceptive information. Furthermore, intratrigeminal connections conserved the somatotopic distribution of primary afferents in the two subnuclei. First, injections of tracer in the dorsomedial and ventrolateral parts of the oral subnucleus resulted in retrograde labelling of the dorsal and ventral parts of the caudal subnucleus respectively. Second, animals that received tracer into the ventrolateral oral subnucleus displayed more caudal labelling than animals that were injected into the dorsomedial oral subnucleus. These findings show the existence of anatomical connections from the caudal part to the oral part of the spinal trigeminal nucleus in the rat. The connections conserve the somatotopic distribution of primary afferents in the two subnuclei. They provide an anatomical substrate for the indirect activation of trigeminal oral subnucleus neurones by somatosensory stimuli through the caudal subnucleus.