Chronic facial inflammatory pain-induced anxiety is associated with bilateral deactivation of the rostral anterior cingulate cortex.

Patients with chronic pain, especially orofacial pain, often suffer from affective disorders, including anxiety. Previous studies largely focused on the role of the caudal anterior cingulate cortex (cACC) in affective responses to pain, long-term potentiation (LTP) in cACC being thought to mediate the interaction between anxiety and chronic pain. But recent evidence indicates that the rostral ACC (rACC), too, is implicated in processing affective pain. However, whether such processing is associated with neuronal and/or synaptic plasticity is still unknown. We addressed this issue in a chronic facial inflammatory pain model (complete Freund's adjuvant model) in rats, by combining behavior, Fos protein immunochemistry and ex vivo intracellular recordings in rACC slices prepared from these animals. Facial mechanical allodynia occurs immediately after CFA injection, peaks at post-injection day 3 and progressively recovers until post-injection days 10-11, whereas anxiety is delayed, being present at post-injection day 10, when sensory hypersensitivity is relieved, but, notably, not at post-injection day 3. Fos expression reveals that neuronal activity follows a bi-phasic time course in bilateral rACC: first enhanced at post-injection day 3, it gets strongly depressed at post-injection day 10. Ex vivo recordings from lamina V pyramidal neurons, the rACC projecting neurons, show that both their intrinsic excitability and excitatory synaptic inputs have undergone long-term depression (LTD) at post-injection day 10. Thus chronic pain processing is associated with dynamic changes in rACC activity: first enhanced and subsequently decreased, at the time of anxiety-like behavior. Chronic pain-induced anxiety might thus result from a rACC deactivation-cACC hyperactivation interplay.

5-HT2A Receptor-Induced Morphological Reorganization of PKCγ-Expressing Interneurons Gates Inflammatory Mechanical Allodynia in Rat.

Mechanical allodynia, a widespread pain symptom that still lacks effective therapy, is associated with the activation of a dorsally directed polysynaptic circuit within the spinal dorsal horn (SDH) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (IIi) interneurons expressing the γ isoform of protein kinase C (PKCγ+) are key elements for allodynia circuits, but how they operate is still unclear. Combining behavioral, ex vivo electrophysiological, and morphological approaches in an adult rat model of facial inflammatory pain (complete Freund's adjuvant, CFA), we show that the mechanical allodynia observed 1 h after CFA injection is associated with the following (1) sensitization (using ERK1/2 phosphorylation as a marker) and (2) reduced dendritic arborizations and enhanced spine density in exclusively PKCγ+ interneurons, but (3) depolarized resting membrane potential (RMP) in all lamina IIi PKCγ+/PKCγ- interneurons. Blocking MDH 5HT2A receptors (5-HT2AR) prevents facial mechanical allodynia and associated changes in the morphology of PKCγ+ interneurons, but not depolarized RMP in lamina IIi interneurons. Finally, activation of MDH 5-HT2AR in naive animals is enough to reproduce the behavioral allodynia and morphological changes in PKCγ+ interneurons, but not the electrophysiological changes in lamina IIi interneurons, induced by facial inflammation. This suggests that inflammation-induced mechanical allodynia involves strong morphological reorganization of PKCγ+ interneurons via 5-HT2AR activation that contributes to open the gate for transmission of innocuous mechanical inputs to superficial SDH/MDH pain circuitry. Preventing 5-HT2AR-induced structural plasticity in PKCγ+ interneurons might represent new avenues for the specific treatment of inflammation-induced mechanical hypersensitivity.SIGNIFICANCE STATEMENT Inflammatory or neuropathic pain syndromes are characterized by pain hypersensitivity such as mechanical allodynia (pain induced by innocuous mechanical stimuli). It is generally assumed that mechanisms underlying mechanical allodynia, because they are rapid, must operate at only the level of functional reorganization of spinal or medullary dorsal horn (MDH) circuits. We discovered that facial inflammation-induced mechanical allodynia is associated with rapid and strong structural remodeling of specifically interneurons expressing the γ isoform of protein kinase C (PKCγ) within MDH inner lamina II. Moreover, we elucidated a 5-HT2A receptor to PKCγ/ERK1/2 pathway leading to the behavioral allodynia and correlated morphological changes in PKCγ interneurons. Therefore, descending 5-HT sensitize PKCγ interneurons, a putative "gate" in allodynia circuits, via 5-HT2A receptor-induced structural reorganization.

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.

[Treating pain after dental surgery: a randomised, controlled, double-blind trial to assess a new formulation of paracetamol, opium powder and caffeine versus tramadol or placebo]. / Traitement de la douleur après avulsion dentaire : essai clinique randomisé en double aveugle comparant deux formulations de paracétamol, caféine et poudre d'opium versus tramadol et placebo.

BACKGROUND: The aim of this study was to evaluate the analgesic efficacy and the safety of the association, paracetamol, opium prepared and caffeine, in two different dosages as compared to the conventional analgesic tramadol hydrochloride, on acute postoperative dental pain. METHODS: We conducted a randomised, double-blind, multicentre, parallel-group clinical trial to test the efficacy and safety of single doses of two associations; paracetamol 500 mg, caffeine 50mg, opium prepared 25, and paracetamol 500 mg, caffeine 50mg, opium prepared 50mg, as compared to tramadol hydrochloride 100mg (called hereafter tramadol 100), and placebo, in the control of postoperative pain following the removal of 2 ipsilateral impacted third molars. The primary efficacy criterion was the sum of pain intensity differences as assessed every 30 minutes within 3 hours after the baseline assessment and administration of study treatment (SPID(0-3h)). RESULTS: Of the 232 randomised patients, 228 (98%) completed the study. Analysis of the primary efficacy criterion (SPID(0-3h)) established: (i) the superiority of the 3 active study treatments vs. placebo (p<0.005); (ii) non-inferiority of paracetamol, caffeine, and opium 25mg, and paracetamol, caffeine, and opium 50mg vs. tramadol. Besides, both formulations of paracetamol, caffeine, and opium showed: (i) a faster onset of analgesic effect as compared to tramadol 100; (ii) a significantly stronger analgesic efficacy than tramadol 100, as measured 1 hour after the treatment intake; this superiority lasted all over the study duration for paracetamol, caffeine, and opium 50mg but not for paracetamol, caffeine, and opium 25mg. No unexpected safety concerns occurred, the two formulations of paracetamol, caffeine, and opium showed a good safety profile especially with paracetamol, caffeine, and opium 25mg as compared to tramadol. DISCUSSION: This study evidenced the non-inferiority of the paracetamol, caffeine, and opium 25mg or 50mg vs. tramadol 100, and even though the strengths of the tested formulations were higher than that of the 2009, commercialised formulation of paracetamol, caffeine, and opium, efficacy was not offset by an alteration of the well recognised safety profile of the less strengthened formulation of the product being in use for decades.

Both oral and caudal parts of the spinal trigeminal nucleus project to the somatosensory thalamus in the rat.

Recent evidence has been accumulated that not only spinal trigeminal nucleus caudalis (Sp5C) neurons but also spinal trigeminal nucleus oralis (Sp5O) neurons respond to noxious stimuli. It is unknown, however, whether Sp5O neurons project to supratrigeminal structures implicated in the sensory processing of orofacial nociceptive information. This study used retrograde tracing with Fluorogold in rats to investigate and compare the projections from the Sp5O and Sp5C to two major thalamic nuclei that relay ascending somatosensory information to the primary somatic sensory cortex: the ventroposteromedial thalamic nucleus (VPM) and the posterior thalamic nuclear group (Po). Results not only confirmed the existence of contralateral projections from the Sp5C to the VPM and Po, with retrogradely labelled neurons displaying a specific distribution in laminae I, III and V, they also showed consistent and similar numbers of retrogradely labelled cell bodies in the contralateral Sp5O. In addition, a topographic distribution of VPM projections from Sp5C and Sp5O was found: neurons in the dorsomedial parts of Sp5O and Sp5C projected to the medial VPM, neurons in the ventrolateral Sp5O and Sp5C projected to the lateral VPM, and neurons in intermediate parts of Sp5O and Sp5C projected to the intermediate VPM. All together, these data suggest that not only the Sp5C, but also the Sp5O relay somatosensory orofacial information from the brainstem to the thalamus. Furthermore, trigemino-VPM pathways conserve the somatotopic distribution of primary afferents found in each subnucleus. These results thus improve our understanding of trigeminal somatosensory processing and help to direct future electrophysiological investigations.

[Neurobiology of trigeminal pain]. / Neurobiologie de la douleur trigéminale.

The brainstem trigeminal complex integrates somatosensory inputs from orofacial areas and meninges. Recent studies have shown the existence of a double representation of pain within the brainstem, at the level of both caudalis and oralis subnuclei. Noxious messages are mainly conveyed by C-fibers that activate the subnucleus caudalis neurons. These neurons in turn activate the subnucleus oralis whose neurons share similar features with the deep spinal dorsal horn neurons. In contrast with the nearness of the laminar organization of the dorsal horn, the vertical organization of the trigeminal complex offers an easier access for the study of segmental mechanisms of nociceptive processing. This model allowed us to show the existence of subtle NMDA-related mechanisms of segmental nocious processing. The trigeminal complex conveys nociceptive messages to several brainstem and thalamic relays that activate a number of cortical areas responsible for pain sensations and reactions. Cortical processing is sustained by reciprocal interactions with thalamic areas and also by a direct modulation of their pre-thalamic relays. The dysfunction of these multiple modulatory mechanisms probably plays a key role in the pathophysiology of chronic trigeminal pain.