Hyperexcitability of muscle spindle afferents in jaw-closing muscles in experimental myalgia: Evidence for large primary afferents involvement in chronic pain.

The goals of this review are to improve understanding of the aetiology of chronic muscle pain and identify new targets for treatments. Muscle pain is usually associated with trigger points in syndromes such as fibromyalgia and myofascial syndrome, and with small spots associated with spontaneous electrical activity that seems to emanate from fibers inside muscle spindles in EMG studies. These observations, added to the reports that large-diameter primary afferents, such as those innervating muscle spindles, become hyperexcitable and develop spontaneous ectopic firing in conditions leading to neuropathic pain, suggest that changes in excitability of these afferents might make an important contribution to the development of pathological pain. Here, we review evidence that the muscle spindle afferents (MSAs) of the jaw-closing muscles become hyperexcitable in a model of chronic orofacial myalgia. In these afferents, as in other large-diameter primary afferents in dorsal root ganglia, firing emerges from fast membrane potential oscillations that are supported by a persistent sodium current (INaP ) mediated by Na+ channels containing the α-subunit NaV 1.6. The current flowing through NaV 1.6 channels increases when the extracellular Ca2+ concentration decreases, and studies have shown that INaP -driven firing is increased by S100ß, an astrocytic protein that chelates Ca2+ when released in the extracellular space. We review evidence of how astrocytes, which are known to be activated in pain conditions, might, through their regulation of extracellular Ca2+ , contribute to the generation of ectopic firing in MSAs. To explain how ectopic firing in MSAs might cause pain, we review evidence supporting the hypothesis that cross-talk between proprioceptive and nociceptive pathways might occur in the periphery, within the spindle capsule.

Limbic Expression of mRNA Coding for Chemoreceptors in Human Brain-Lessons from Brain Atlases.

Animals strongly rely on chemical senses to uncover the outside world and adjust their behaviour. Chemical signals are perceived by facial sensitive chemosensors that can be clustered into three families, namely the gustatory (TASR), olfactory (OR, TAAR) and pheromonal (VNR, FPR) receptors. Over recent decades, chemoreceptors were identified in non-facial parts of the body, including the brain. In order to map chemoreceptors within the encephalon, we performed a study based on four brain atlases. The transcript expression of selected members of the three chemoreceptor families and their canonical partners was analysed in major areas of healthy and demented human brains. Genes encoding all studied chemoreceptors are transcribed in the central nervous system, particularly in the limbic system. RNA of their canonical transduction partners (G proteins, ion channels) are also observed in all studied brain areas, reinforcing the suggestion that cerebral chemoreceptors are functional. In addition, we noticed that: (i) bitterness-associated receptors display an enriched expression, (ii) the brain is equipped to sense trace amines and pheromonal cues and (iii) chemoreceptor RNA expression varies with age, but not dementia or brain trauma. Extensive studies are now required to further understand how the brain makes sense of endogenous chemicals.

Early Hypoexcitability in a Subgroup of Spinal Motoneurons in Superoxide Dismutase 1 Transgenic Mice, a Model of Amyotrophic Lateral Sclerosis.

In amyotrophic lateral sclerosis (ALS), large motoneurons degenerate first, causing muscle weakness. Transgenic mouse models with a mutation in the gene encoding the enzyme superoxide dismutase 1 (SOD1) revealed that motoneurons innervating the fast-fatigable muscular fibres disconnect very early. The cause of this peripheric disconnection has not yet been established. Early pathological signs were described in motoneurons during the postnatal period of SOD1 transgenic mice. Here, we investigated whether the early changes of electrical and morphological properties previously reported in the SOD1G85R strain also occur in the SOD1G93A-low expressor line with particular attention to the different subsets of motoneurons defined by their discharge firing pattern (transient, sustained, or delayed-onset firing). Intracellular staining and recording were performed in lumbar motoneurons from entire brainstem-spinal cord preparations of SOD1G93A-low transgenic mice and their WT littermates during the second postnatal week. Our results show that SOD1G93A-low motoneurons exhibit a dendritic overbranching similar to that described previously in the SOD1G85R strain at the same age. Further we found an hypoexcitability in the delayed-onset firing SOD1G93A-low motoneurons (lower gain and higher voltage threshold). We conclude that dendritic overbranching and early hypoexcitability are common features of both low expressor SOD1 mutants (G85R and G93A-low). In the high-expressor SOD1G93A line, we found hyperexcitability in the sustained firing motoneurons at the same period, suggesting a delay in compensatory mechanisms. Overall, our results suggest that the hypoexcitability indicate an early dysfunction of the delayed-onset motoneurons and could account as early pathological signs of the disease.

Expression of the Cerebral Olfactory Receptors Olfr110/111 and Olfr544 Is Altered During Aging and in Alzheimer's Disease-Like Mice.

A growing number of studies report the expression of olfactory receptors (ORs) in many non-chemosensory tissues and organs. However, within the brain, very few ectopic ORs are exhaustively documented. Their kinetic expression, cellular localization, and functions remain elusive. Using cDNA microarrays, quantitative PCR, and immunohistochemistry, we studied the cellular and sub-cellular localization of Olfr110/111 and Olfr544 and their timely expression in various brain areas of wild-type and transgenic Alzheimer's disease-like (5xFAD) mice. We observed that Olfr110/111 and Olfr544 proteins are mainly expressed by neurons in cortical and hippocampal regions and, to a lesser extent, by astrocytes, microglia, oligodendrocytes, and endothelial cells. In addition, both ORs are present at the cell membrane and co-expressed with the olfactory Gαolf protein, suggesting that they can be functional. Remarkably, we also found that the expression of the mRNA encoding for Olfr110/111 tends to increase with age in both the cortex and hippocampus of wild-type and transgenic mice. Moreover, Olfr110/111 transcript expression is markedly impaired in the brain of Alzheimer's disease-like mice. A different profile is noticed for Olfr544, for which an overexpression is observed only in the cortex of 9-month-old animals. In addition, in transgenic mice, olfactory receptors are observed near amyloid plaques. Altogether, our findings indicate that ORs may play a role in brain functioning, in normal and pathological conditions.