Migraine in multiple sclerosis and other chronic inflammatory diseases.

Migraine is a very prevalent disease worldwide and is a major cause of disability. As known for a long time, migraine is associated with neurogenic inflammation. Epidemiological studies have shown that migraine is comorbid with several chronic inflammatory diseases, including multiple sclerosis (MS), chronic inflammatory rheumatic diseases (CIRDs) and inflammatory bowel diseases (IBDs). This brief narrative review highlights some recent data supporting a link between migraine and these three chronic inflammatory diseases. Studies found that migraine prevalence is approximately two-fold higher in these diseases compared to the general population. The causal link between migraine and these chronic inflammatory diseases has not been identified yet. Here, we suggest that systemic mediators (such as cytokines) and gut microbiome make migraine worse or add significant risks. Systemic inflammation biomarkers and gut microbiome modification are certainly avenues worth exploring.

Model-based signal processing enables bidirectional inferring between local field potential and spikes evoked by noxious stimulation.

BACKGROUND: Recording spontaneous and evoked activities by means of unitary extracellular recordings and local field potential (LFP) are key understanding the mechanisms of neural coding. The LFP is one of the most popular and easy methods to measure the activity of a population of neurons. LFP is also a composite signal known to be difficult to interpret and model. There is a growing need to highlight the relationship between spiking activity and LFP. Here, we hypothesized that LFP could be inferred from spikes under evoked noxious conditions. METHOD: Recording was performed from the medullary dorsal horn (MDH) in deeply anesthetized rats. We detail a process to highlight the C-fiber (nociceptive) evoked activity, by removing the A-fiber evoked activity using a model-based approach. Then, we applied the convolution kernel theory and optimization algorithms to infer the C-fiber LFP from the single cell spikes. Finally, we used a probability density function and an optimization algorithm to infer the spikes distribution from the LFP. RESULTS: We successfully extracted C-fiber LFP in all data recordings. We observed that C-fibers spikes preceded the C-fiber LFP and were rather correlated to the LFP derivative. Finally, we inferred LFP from spikes with excellent correlation coefficient (r = 0.9) and reverse generated the spikes distribution from LFP with good correlation coefficients (r = 0.7) on spikes number. CONCLUSION: We introduced the kernel convolution theory to successfully infer the LFP from spikes, and we demonstrated that we could generate the spikes distribution from the LFP.

Migraine prevalence in inflammatory bowel disease patients: A tertiary-care centre cross-sectional study.

BACKGROUND: Inflammatory bowel diseases (IBD) are systemic, chronic inflammatory conditions that predominately affect the gastrointestinal tract and can induce abdominal pain. Besides, many IBD patients complain about headaches in daily practice. The objective was to assess the prevalence of headaches, including migraines and pain with neuropathic characteristics (NC), in IBD patients compared to historical controls from the general population. METHODS: Overall, 203 consecutive tertiary-care centre patients completed validated self-administered questionnaires and benefitted from a clinical evaluation performed by an IBD physician at the same time. RESULTS: In our cohort, 75% of the patients experienced pain in the previous 3 months. Migraine prevalence was two-fold higher in IBD patients compared to the general population (41% vs. 21.3%, p < 0.001). Migraine was associated with a younger age, female gender and higher depression scores. Although migraine impact was very important for 30% of the patients (61/203), specific acute therapeutics were prescribed in only 22% of cases (18/83). Chronic pain with NC was more frequent than in the general population (11.3% vs. 6.9%, p = 0.012) and was strongly associated with the presence of extra-intestinal manifestations (p < 0.001). Abdominal pain concerned 19% of the patients during the previous week and was, as expected, associated with disease activity. CONCLUSIONS: Migraine prevalence is strongly increased in IBD patients followed in tertiary care. A systematic screening for migraine should be done by IBD physicians in daily practice to provide adequate therapeutics. Further studies are needed to confirm whether migraine should be classified as IBD extra-intestinal manifestations. SIGNIFICANCE: Migraine prevalence was two-fold higher in IBD patients compared to the general population, was generally poorly treated and a systematic screening for migraine should be done by IBD physicians in daily practice to provide adequate therapeutics.

Relationship between adaptation and cardiovascular response to tonic cold and heat pain Adaptability to tonic pain and cardiovascular responses.

BACKGROUND: The mechanisms of adaptation to tonic pain are not elucidated. We hypothesized that the adaptability to tonic pain is related to the cardiovascular system. METHODS: Twenty-six subjects received over two sessions in a random order: tonic cold (7 ± 0.2 °C) and heat pain (47.5 ± 0.5 °C) on the hand for 5 min. Pain intensity, blood pressure (BP), and heart rate (HR) were continuously monitored. RESULTS: Pain experience during the heat (HIT) and cold (CIT) immersion tests exhibited different average time courses, being approximated with a linear and cubic function, respectively. In each test, two groups of participants could be identified based on the time course of their tonic thermal pain: one-third of participants were pain adaptive and two-thirds non adaptive. The adaptive group exhibited higher initial pain, lower last pain, and shorter latency to peak pain than the non-adaptive one. Interestingly, some participants were adaptive to both pain stimuli, most were not. HIT as well as CIT produced a stable elevation of BP. However, BP was higher during CIT than HIT (p = 0.034). HR was also increased during CIT and HIT, but the two tests differed with respect to the time course of responses. Finally, the intensity and time course of pain rating to both HIT and CIT correlated with neither BP nor HR responses. CONCLUSIONS: These results suggest that individual sensitivity and adaptability to tonic thermal pain is related to the intensity of initial pain rating and the latency to peak pain but not to cardiovascular responses.

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.

Are there differences between cephalic and extracephalic cutaneous allodynia in migraine patients?

Cutaneous allodynia (CA), pain in response to innocuous cutaneous stimuli, is recognized as a sign of central sensitization during migraine episodes. It is either restricted within the pain area on the ipsilateral head, or extends within and outside the head. Moreover, CA can be elicited in response to thermal (heat or cold) and/or mechanical stimuli. This raises the question as to whether cephalic and extracephalic CAs share the same properties. We assessed cephalic and extracephalic CAs in migraine episodic patients using a questionnaire completed at home during migraine attacks. A total of 67 episodic migraine patients (58 women, nine men; 4013 years old) addressed all questions in the questionnaire. Forty-nine patients (73%) cited one or more allodynic symptoms during or immediately after the migraine attack. Almost all 49 patients reported cephalic CA, whereas 24 (49%) also reported extracephalic CA. Occurrence and extension of CA correlated (P = 0.005) with headache intensity. Modalities of cephalic and extracephalic CA were different (chi2 = 12.03; P = 0.002), extracephalic CA being mostly thermal (75%) whereas cephalic CA was mostly mechanical (92%). This suggests that cephalic and extracephalic CAs involve different mechanisms.

A role for wind-up in trigeminal sensory processing: intensity coding of nociceptive stimuli in the rat.

Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres. The correlate of wind-up in humans is temporal summation, which is an increase in pain perception to repetitive constant nociceptive stimulation. Although wind-up is widely used as a tool for studying the processing of nociceptive information, including central sensitization, its actual role is still unknown. Here, we recorded from trigeminal WDR neurons using in vivo electrophysiological techniques in rats and assessed the wind-up phenomenon in response to stimuli of different intensities and frequencies. First, we found that the amplitude of C-evoked responses of WDR neurons to repetitive stimulation increased progressively to reach a peak, then consistently showed a stable or slightly decreasing plateau phase. Only the first phase of this time course fitted in with the wind-up description. Therefore, to assess wind-up, we measured a limited number of initial responses. Second, we showed that wind-up, i.e. the slope of the frequency-dependent increase in the response to C-fibre stimulation, was linearly correlated to the stimulus intensity. Intensities of brief C-fibre inputs were thus coded into frequencies of action potentials by second-order neurons through frequency-dependent potentiation of the evoked responses. Third, wind-up also occurred at stimulation intensities below the threshold for C-evoked responses in WDR neurons, suggesting that wind-up can amplify subthreshold C-fibre inputs to WDR neurons. This might account for the observation that sparse, subliminal, neuronal activity in nociceptors can become painful via central integration of neural responses. Altogether, the present results show that wind-up can provide trigeminal WDR neurons with the capability to encode the intensity of short-duration orofacial nociceptive stimuli and to detect subthreshold nociceptive input. Thus, not only may wind-up play a physiological role in trigeminal sensory processing, but its enhancement may also underlie the pathophysiology of chronic orofacial pain conditions.

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.

Organization of diencephalic projections from the spinal trigeminal nucleus oralis: an anterograde tracing study in the rat.

The organization of the efferent projections from the spinal trigeminal nucleus oralis (Sp5O) to the diencephalon was studied in the rat using the anterograde tracer Phaseolus vulgaris leucoagglutinin. The present study confirms the existence of trigemino-thalamic pathways originating from the Sp5O and details their distribution. The main diencephalic targets of the Sp5O are the ventral posteromedial thalamic nucleus (VPM), the posterior thalamic nuclei (Po) and the ventral part of the zona incerta (ZIv), contralaterally, and the parvicellular part of the ventral posterior thalamic nucleus (VPpc), bilaterally. The distribution of these projections varies according to the dorso-ventral location of the injection sites: the dorsal part of the Sp5O projects to the medial part of the VPM and the Po, and to the caudal part of the ZIv, as well as to the VPpc. The ventral part of the Sp5O projects to the lateral part of the VPM and the Po and to the rostral part of the ZIv. These results suggest that the trigemino-diencephalic pathways originating from the Sp5O are involved in the processing of gustatory and somatosensory information.

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.

A human oral capsaicin pain model to assess topical anesthetic-analgesic drugs.

Repeated application of capsaicin on the tongue has been used as a human oral pain model to assess topical anesthetic-analgesic drugs. The reliability of the model was evaluated by observing the variability of the response to repeated applications of capsaicin after three successive sessions at 1 day intervals. No session effect was observed for the time course of the visual analogue scale (VAS) scores and the area under the curve, but a significant decrease of VAS peak scores was noted from the first to the third session. The sensitivity of the model was assessed by mouth rinses with three doses of lidocaine (0.25, 0.5 and 1%). Lidocaine significantly reduced the burning pain. This effect was rapid, reversible and dose dependent. It is concluded that the oral capsaicin pain model displays good reliability and sensitivity and allows safe evaluation of candidate topical analgesic and anesthetic drugs.

Strychnine alters response properties of trigeminal nociceptive neurons in the rat.

The purpose of this study was to examine the role of glycine in sensory processes in the spinal trigeminal nucleus oralis (Sp5O). We evaluated the effect of intravenous administration of strychnine, a glycine receptor antagonist, on the responses of Sp5O convergent neurons evoked by innocuous peripheral electrical and mechanical stimuli in halothane-anesthetized rats. Strychnine significantly increased the Abeta-fiber-evoked activities of Sp5O neurons to electrical stimulation in a dose-dependent (0.2-0.8 mg/kg) fashion. The response to air-jet stimulation was also significantly enhanced at the highest dose of strychnine. These findings indicate that glycinergic neurons participate in the control of the flow of information conveyed to Sp5O nociceptive neurons by myelinated low-threshold mechanoreceptive afferents. Thus, alteration of trigeminal glycinergic modulation may contribute to the dynamic mechanical allodynia that occurs in trigeminal neuropathies.

Systemic morphine reduces the wind-up of trigeminal nociceptive neurons.

We assessed the effects of intravenous morphine on the wind-up of nociceptive neurons of the spinal trigeminal nucleus oralis (Sp5O). Extracellular recordings of Sp5O nociceptive convergent neurons were performed in intact halothane-anesthetized rats. Wind-up of C-fiber-evoked responses was elicited by repetitive electrical stimulation (train of 16 shocks, 0.66 Hz) of their receptive field at C-fiber intensity (3 times the threshold). Wind-up was tested for its sensitivity to morphine (6 mg/kg,i.v.), and the specificity of the effects was verified with naloxone (0.4 mg/kg, i.v.). Nineteen convergent neurons displaying wind-up were recorded. Morphine reduced the wind-up of all but one. In five cases, notwithstanding a reduced wind-up, the neuronal response evoked by the first stimulus in the train (initial input) was unexpectedly increased. Naloxone always antagonized morphine inhibitory effects on the wind-up. When administered systemically, morphine reduced the wind-up of trigeminal nociceptive neurons. This inhibitory effect occurred independently of morphine's ability to affect the initial C-fiber-evoked input. Our findings support the idea that systemic morphine probably blocks wind-up by acting at opioid receptors located postsynaptically to nociceptive primary afferents.

Towards a pain treatment based on the identification of the pain-generating mechanisms?

Despite continuous improvements in available pain treatments, many patients with chronic pain still remain insufficiently relieved. Although such therapeutic failures are often ascribed to pharmacological or psychological factors, difficulties in elucidating pain-generating mechanisms may be the main cause of insufficient pain management. These difficulties arise from several origins, including the unsuitability of the usual classification of pain, the exclusive use of etiology or symptom criteria as the main dimension of pain to guide the choice of therapeutic agents, the inadequate interpretation of sensory deficit, the lack of identification of the injured tissues, the absence of objective pain assessment by psychophysical methods. In this paper, we review briefly some fundamental knowledge to determine pain treatment based on the identification of the physiopathological mechanisms of pain. We advocate that once pain-generating mechanisms are known, it becomes possible to establish the appropriate treatment of pain.

[Towards a pain treatment based on the identification of the physiopathological mechanisms]. / Vers une stratégie antalgique fondée sur l'identification des mécanismes physiopathologiques.

The selection of a pain treatment should be based on the identification of the mechanisms of its origin. Nowadays, many patients with chronic pain continue to suffer severe pain. Failure to obtain a satisfactory response is often ascribed to individual peculiarities in drug metabolism, tolerance, resistance to common analgesics or to psychological factors. However, difficulties in elucidating pain-generating mechanisms may be the main source of insufficient pain management. These difficulties can be explained by several factors including: the unsuitability of the usual classification of pain, the use of etiology and symptom criteria as the main dimension of pain to guide the choice of therapeutic agent, the inadequate interpretation of sensory deficit, the lack of identification of the injured tissues and the lack of use of psychophysical methods to assess pain. This article reviews some fundamental knowledge to determine pain treatment based on the identification of the physiopathological mechanisms of pain.

Differential effects of trigeminal tractotomy on Adelta- and C-fiber-mediated nociceptive responses.

In this study we have tested in the rat, whether trigeminal tractotomy, which deprives the spinal trigeminal nucleus caudalis (Sp5C) of its trigeminal inputs, affected differentially nociceptive responses mediated by C- vs. Adelta-nociceptors from oral and perioral regions. Tractotomy had no effect on the threshold of the jaw opening reflex, induced by incisive pulp stimulation (Adelta-fiber-mediated), but blocked the formalin response (mainly C-fiber-mediated). These results suggest that nociceptive responses mediated by trigeminal C-fibers completely depend on the integrity of the Sp5C, while intraoral sensations triggered Adelta-fibers (especially of dental origin) are primarily processed in the rostral part of the spinal trigeminal nucleus.

Stimulus-function, wind-up and modulation by diffuse noxious inhibitory controls of responses of convergent neurons of the spinal trigeminal nucleus oralis.

Extracellular unitary recordings were made from 53 spinal trigeminal nucleus oralis (Sp5O) convergent neurons in halothane-anaesthetized rats. The neurons had an ipsilateral receptive field including mainly oral or perioral regions. They responded to percutaneous electrical stimulation with two peaks of activation. The first had a short latency (4.3 +/- 0.3 ms) and low threshold (0.35 +/- 0.04 mA), whereas the second had a longer latency (68.1 +/- 3.4 ms) and higher threshold (7.3 +/- 0.5 mA). Intracutaneous injection of capsaicin (0.1%) produced a strong and rapid reduction of the long-latency responses of Sp5O convergent neurons with little effect on the short-latency responses. In most cases (73%), the long-latency responses exhibited a wind-up phenomenon during repetitive (0.66 Hz) suprathreshold electrical stimulation. These results suggest that C-fibres mediate the long-latency response of Sp5O convergent neurons. Regarding the C-fibre-evoked responses, a linear relationship between the intensity of the applied current and the magnitude of the response was found within the one to three times threshold range. The Sp5O convergent neurons also encoded the intensity of mechanical stimuli applied to the skin or mucosa in the 5-50 g ranges. The evoked activity of Sp5O convergent neurons could be suppressed by noxious heat applied to the tail (52 degrees C) and long-lasting poststimulus effects followed this. These findings show that convergent neurons in the Sp5O resemble those in the deep laminae of the spinal dorsal horn and spinal trigeminal nucleus caudalis, and further support that the Sp5O plays a part in the processing of nociceptive information from the orofacial region.

Morphine microinjected into the nucleus raphe magnus does not block the activity of spinal trigeminal nucleus oralis convergent neurons in the rat.

This study investigated the effects of morphine microinjection into the nucleus raphe magnus (RMg) on electrically evoked C-fiber activities of convergent neurons in the spinal trigeminal nucleus oralis (Sp5O), in halothane-anesthetized rats. Although the neurons could be depressed by systemic morphine (6 mg/kg, i.v.) in a naloxone-reversible fashion, morphine microinjected into the RMg (2. 5 microgram or 5 microgram) neither depressed their C-fiber-evoked responses, nor the diffuse noxious inhibitory controls acting on them. It is concluded that the RMg is not involved in reinforcing descending inhibitory controls that are tonic or triggered by noxious stimuli acting on Sp5O convergent neurons.

Morphine administered in the substantia gelatinosa of the spinal trigeminal nucleus caudalis inhibits nociceptive activities in the spinal trigeminal nucleus oralis.

The present study investigates the effects of morphine microinjection into the spinal trigeminal nucleus caudalis (Sp5C) or the spinal trigeminal nucleus oralis (Sp5O) on C-fiber-evoked activities of Sp5O convergent neurons, after supramaximal percutaneous electrical stimulation in halothane-anesthetized rats. When it was microinjected into the Sp5O, morphine (2.5 microg in 0. 25 microl) never depressed the C-fiber-evoked responses of Sp5O convergent neurons (n = 13), whereas these neurons were responsive to the inhibitory effects of systemic morphine (6 mg/kg, i.v.) in a naloxone-reversible manner. On the contrary, morphine microinjected into the Sp5C produced a naloxone-reversible inhibition of the C-fiber-evoked responses of Sp5O neurons (n = 14). The magnitude and the time course of this effect varied according to the location of the injection sites. After microinjection into the superficial laminae (n = 7), a strong depressive effect of morphine (7 +/- 5% of control) on the C-fiber-evoked responses was apparent as soon as 5 min after the injection and could always be reversed by naloxone, administered either intravenously (0.4 mg/kg) or locally (2.5 microg in 0.6 microl) at the same site as morphine. After microinjection into deeper laminae (V-VI), a significant depressive effect (34 +/- 5% of control) of morphine could be detected only 20 min after the injection and was reversed only by intravenous administration of naloxone. These results suggest that morphine exerts its antinociceptive action on Sp5O convergent neurons by blocking the C-fiber inputs that relay in the Sp5C substantia gelatinosa. The mechanisms that underlie the activation of Sp5O convergent neurons by C-fibers and the inhibition of C-fiber-evoked responses of Sp5O convergent neurons by morphine microinjected into the Sp5C are discussed.