Alain Artola

General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression.

Summary Progressively impaired descending inhibition and potentiated general trigeminospinal hypersensitivity participate in the worsening, spatial spreading persistence of cutaneous allodynia, upon repeated dural nociception, in rats. ABSTRACT Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low‐ and high‐intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high‐intensity, but not low‐intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low‐intensity stimulation, too, induces a reversible cephalic allodynia, and high‐intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high‐intensity stimulation. Fos expression reveals that a single high‐intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition‐induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine.

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

&NA; The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2‐like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2‐like receptors inhibits, whereas blocking them enhances, both formalin‐ and capsaicin‐evoked pain behavior and C‐fiber‐evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C‐fiber‐evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2‐like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2‐like receptors at the level of superficial medullary dorsal horn. Such dopamine‐dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms—spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these. Descending dopaminergic controls exert a tonic inhibition of trigeminal nociceptive information via D2‐like receptors within superficial medullary dorsal horn. Dopamine‐dependent tonic inhibition is dynamically modulated by pain.

Bilateral descending hypothalamic projections to the spinal trigeminal nucleus caudalis in rats.

Several lines of evidence suggest that the hypothalamus is involved in trigeminal pain processing. However, the organization of descending hypothalamic projections to the spinal trigeminal nucleus caudalis (Sp5C) remains poorly understood. Microinjections of the retrograde tracer, fluorogold (FG), into the Sp5C, in rats, reveal that five hypothalamic nuclei project to the Sp5C: the paraventricular nucleus, the lateral hypothalamic area, the perifornical hypothalamic area, the A11 nucleus and the retrochiasmatic area. Descending hypothalamic projections to the Sp5C are bilateral, except those from the paraventricular nucleus which exhibit a clear ipsilateral predominance. Moreover, the density of retrogradely FG-labeled neurons in the hypothalamus varies according to the dorso-ventral localization of the Sp5C injection site. There are much more labeled neurons after injections into the ventrolateral part of the Sp5C (where ophthalmic afferents project) than after injections into its dorsomedial or intermediate parts (where mandibular and maxillary afferents, respectively, project). These results demonstrate that the organization of descending hypothalamic projections to the spinal dorsal horn and Sp5C are different. Whereas the former are ipsilateral, the latter are bilateral. Moreover, hypothalamic projections to the Sp5C display somatotopy, suggesting that these projections are preferentially involved in the processing of meningeal and cutaneous inputs from the ophthalmic branch of the trigeminal nerve in rats. Therefore, our results suggest that the control of trigeminal and spinal dorsal horn processing of nociceptive information by hypothalamic neurons is different and raise the question of the role of bilateral, rather than unilateral, hypothalamic control.

NK1 receptor-expressing spinoparabrachial neurons trigger diffuse noxious inhibitory controls through lateral parabrachial activation in the male rat

ABSTRACT Diffuse noxious inhibitory controls (DNIC) are very powerful long‐lasting descending inhibitory controls, which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. The principal feature of DNIC is that they are subserved by a loop that involves supraspinal structures that have not yet been identified. Using behavioral, in vivo extracellular electrophysiological and anatomical approaches, we studied the neuronal network underlying DNIC. Using a new behavioral model of DNIC, in which facial grooming produced by formalin injection into the vibrissa pad is inhibited by a conditioning noxious stimulation, formalin injection into the hindpaw, we show that blockade of NK1 receptors in the lumbar spinal cord – by intrathecal administration of the NK1 receptor antagonist, RP67580 – largely attenuates DNIC‐induced facial analgesia. In a second series of experiments, WDR neurons were recorded from the trigeminal subnucleus oralis and inhibited their C‐fiber‐evoked responses by the conditioning noxious heat stimulation of the hindpaw. We show that inactivating the lateral parabrachial area – by microinjecting the GABAA agonist, muscimol – strongly attenuates DNIC‐induced inhibition of C‐fiber‐evoked responses. Finally, our neuroanatomical tracing study demonstrates that the descending pathway for DNIC does not involve direct descending projections from the PB area. We conclude that (1) lamina I/III spinoparabrachial neurons that express the NK1 receptor and (2) parabrachial neurons are involved in the ascending part of the loop underlying DNIC and that the descending pathway for DNIC might include indirect projections to the spinal or medullary dorsal horn.

Organization of projections from the spinal trigeminal subnucleus oralis to the spinal cord in the rat: a neuroanatomical substrate for reciprocal orofacial-cervical interactions.

The organization of efferent projections from the spinal trigeminal nucleus oralis (Sp5O) to the spinal cord in the rat was studied using the anterograde tracer Phaseolus vulgaris leucoagglutinin. Sp5O projections to the spinal cord are restricted to the cervical cord. No labeled terminal can be detected in the thoracic and lumbar cord. The organization of these projections happens to critically depend on the dorso-ventral location of the injection site. On the one hand, the dorsal part of the Sp5O projects to the medial part of the dorsal horn (laminae III-V) at the C1 level, on the ipsilateral side, and to the ventral horn, on both sides but mainly on the ipsilateral one. Ipsilateral labeled terminals are distributed throughout laminae VII to IX but tend to cluster around the dorso-medial motor nuclei, especially at C3-C5 levels. Within the contralateral ventral horn, label terminals are found particularly in the region of the ventro-medial motor nucleus. This projection extends as far caudally as C3 or C4 level. On the other hand, the ventral part of the Sp5O projects to the lateral part of the dorsal horn (laminae III-V) at the C1 level, on the ipsilateral side, and to the ventral horn, on both sides but mainly on the contralateral one. Contralateral labeled terminals are distributed within the region of the dorso- and ventro-medial motor nuclei at C1-C4 levels whereas they are restricted to the dorso-medial motor nucleus at C5-C8 levels. These findings suggest that Sp5O is involved in the coordination of neck movements and in the modulation of incoming sensory information at the cervical spinal cord.

Protein kinase C gamma interneurons in the rat medullary dorsal horn: Distribution and synaptic inputs to these neurons, and subcellular localization of the enzyme

The γ isoform of protein kinase C (PKCγ), which is concentrated in interneurons in the inner part of lamina II (IIi) of the dorsal horn, has been implicated in the expression of tactile allodynia. Lamina IIi PKCγ interneurons were shown to be activated by tactile inputs and to participate in local circuits through which these inputs can reach lamina I, nociceptive output neurons. That such local circuits are gated by glycinergic inhibition and that A‐ and C‐fibers low threshold mechanoreceptors (LTMRs) terminate in lamina IIi raise the general issue of synaptic inputs to lamina IIi PKCγ interneurons. Combining light and electron microscopic immunochemistry in the rat spinal trigeminal nucleus, we show that PKCγ‐immunoreactivity is mostly restricted to interneurons in lamina IIi of the medullary dorsal horn, where they constitute 1/3 of total neurons. The majority of synapses on PKCγ‐immunoreactive interneurons are asymmetric (likely excitatory). PKCγ‐immunoreactive interneurons appear to receive exclusively myelinated primary afferents in type II synaptic glomeruli. Neither large dense core vesicle terminals nor type I synaptic glomeruli, assumed to be the endings of unmyelinated nociceptive terminals, were found on these interneurons. Moreover, there is no vesicular glutamate transporter 3‐immunoreactive bouton, specific to C‐LTMRs, on PKCγ‐immunoreactive interneurons. PKCγ‐immunoreactive interneurons contain GABAAergic and glycinergic receptors. At the subcellular level, PKCγ‐immunoreactivity is mostly concentrated on plasma membranes, close to, but not within, postsynaptic densities. That only myelinated primary afferents were found to contact PKCγ‐immunoreactive interneurons suggests that myelinated, but not unmyelinated, LTMRs play a critical role in the expression of mechanical allodynia. J. Comp. Neurol. 522:393–413, 2014.

Segmental disinhibition suppresses C-fiber inputs to the rat superficial medullary dorsal horn via the activation of GABAB receptors

Specialized primary afferents, although they terminate in different laminae within the dorsal horn (DH), are known to interact through local circuit excitatory and inhibitory neurons. That a loss of segmental inhibition probably contributes to persistent pain hypersensitivity during chronic pain raises the question as to how disinhibition‐induced changes in cross‐modal interactions account for chronic pain symptoms. We sought to characterize how pharmacological blockade of glycine and gamma‐aminobutyric acid (GABA) receptors modifies synaptic transmission between primary afferent fibers and second‐order neurons by recording field potentials in the superficial medullary dorsal horn (MDH) of anesthetized rats. Transcutaneous electrical stimulation evokes three negative field potentials elicited by, from earliest to latest, Aβ‐, Aδ‐ and C‐fiber primary afferents. Blocking segmental glycine and/or GABAA receptors, with strychnine and bicuculline, respectively, strongly facilitates Aβ‐ and Aδ‐fiber‐evoked polysynaptic field potentials but, conversely, inhibits, or even abolishes, the whole C‐fiber field potential. Blocking segmental GABAB receptors, with phaclofen, reverses such suppression of C‐fiber field potentials. Interestingly, it also potentiates C‐fiber field potentials under control conditions. Finally, activation of segmental GABAB receptors, with baclofen, preferentially inhibits C‐fiber field potentials. Our results suggest that activation of A‐fiber primary afferents inhibits C‐fiber inputs to the MDH by the way of polysynaptic excitatory pathways, last‐order GABAergic interneurons and presynaptic GABAB receptors on C‐fiber primary afferents. Under physiological conditions, activation of such local DH circuits is closely controlled by segmental inhibition but it might contribute to paradoxically reduced pain hypersensitivity under pathological disinhibition.

The nucleus raphe magnus OFF-cells are involved in diffuse noxious inhibitory controls.

Diffuse noxious inhibitory controls (DNIC) are very powerful long-lasting descending inhibitory controls which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. DNIC are subserved by a loop involving supraspinal structures such as the lateral parabrachial nucleus and the subnucleus reticularis dorsalis. Surprisingly, though, whether the nucleus raphe magnus (NRM), another supraspinal area which is long known to be important in pain modulation, is involved in DNIC is still a matter of discussion. Here, we reassessed the role of the NRM neurons in DNIC by electrophysiologically recording from wide dynamic range (WDR) neurons in the trigeminal subnucleus oralis and pharmacologically manipulating the NRM OFF- and ON-cells. In control conditions, C-fiber-evoked responses in trigeminal WDR neurons are inhibited by a conditioning noxious heat stimulation applied to the hindpaw. We show that inactivating the NRM by microinjecting the GABAA receptor agonist, muscimol, both facilitates C-fiber-evoked responses of trigeminal WDR neurons and strongly attenuates their inhibition by heat applied to the hindpaw. Interestingly, selective blockade of ON-cells by microinjecting the broad-spectrum excitatory amino acid antagonist, kynurenate, into the NRM neither affects C-fiber-evoked responses nor attenuates DNIC of trigeminal WDR neurons. These results indicate that the NRM tonically inhibits trigeminal nociceptive inputs and is involved in the neuronal network underlying DNIC. Moreover, within NRM, OFF-cells might be more specifically involved in both the tonic and phasic descending inhibitory controls of trigeminal nociception.

Etiology, distribution, treatment modalities and complications of maxillofacial fractures

Purpose: This study evaluated the trends and factors associated with maxillofacial fractures treated from 1997 to 2007 in the Oral and Maxillofacial Surgery Department of the Clermont-Ferrand University Hospital. Material and Methods: This study included 364 patients of which 82% were men and 45%, 20-29-years old. The etiology, anatomical distribution, treatment modality and complications of maxillofacial fractures were examined. Results: Overall, interpersonal violence, traffic accidents and falls were the most common mechanisms of injury. There was a decreasing trend in traffic accidents and increasing one in falls as a cause of fracture over the 11-years period of this study. Young male patients were preferentially victim of interpersonal violence and traffic accidents, while middle-aged ones were of falls and work-related accidents. Middle-aged female patients were preferentially victim of traffic accidents and interpersonal violence, while older ones were of falls. And the number of fractures per patient varied according to the mechanism of injury: low after work-related accidents and high after traffic accidents. About two-third of fractures involved the mandible. Most of these mandibular fractures were treated by osteosynthesis with or without intermaxillary fixation, with the proportion of the latter increasing over time. There were very few postoperative infections and only in mandible. Conclusions: Maxillofacial fractures predominantly occur in young men, due to interpersonal violence. There is nevertheless an increasing trend in falls as a cause of fracture, especially in female patients, consistent with the increasing trend in presentation of older people. Most maxillofacial fractures involve the mandible and there is an increasing trend in treating these fractures by osteosynthesis without intermaxillary fixation. Antibiotic prophylaxis associated with dental hygiene care can be indicated to prevent postoperative infections. Key words:Maxillofacial fractures, Epidemiology, Trends, Influencing factors, Fall, Age, Gender, Antibiotic prophylaxis.

Propranolol treatment prevents chronic central sensitization induced by repeated dural stimulation

Abstract Migraine is currently conceptualized as a chronic disease with episodic manifestations. In some patients, migraine attack frequency increases, leading to chronic migraine. Daily preventive therapy is initiated to decrease attack frequency. Propranolol, a first-line medication for migraine prophylaxis, reduces attack frequency in nearly 50% of patients receiving it. However, the mechanisms of its antimigraine action are unclear. We examined the effect of daily propranolol treatment (10 mg·kg−1 per os, 8 days) in a rat model of recurrent activation of dural nociceptors (repeated infusion of an inflammatory soup (IS) on the dura through a cannula every 2-3 days). Propranolol does not abort IS-induced acute cephalic mechanical allodynia but blocks the development of a chronic cutaneous hypersensitivity upon repeated IS injections. Furthermore, propranolol prevents (1) the elevated touch-evoked Fos expression within the trigeminocervical complex, (2) enhanced both spontaneous activity, and evoked responses of second-order trigeminovascular neurons, (3) elevated touch-evoked rostral ventromedial medulla and locus coeruleus Fos expression and (4) diffuse noxious inhibitory controls impairment, induced by repeated IS injections. Our results suggest that propranolol exerts its prophylactic action, at least in part, by blocking the chronic sensitization of descending controls of pain, arising from the rostral ventromedial medulla and locus coeruleus, and in turn preventing the maintenance of a state of facilitated trigeminovascular transmission within the trigeminocervical complex. Assessing changes in these brain areas has the potential to elucidate the mechanisms for migraine transformation and to reveal novel biological and molecular targets for specific migraine-preventive therapies.