Chronic Neuropathic Orofacial Pain Research Articles

Epigenetic HDAC5 Inhibitor Reverses Craniofacial Neuropathic Pain in Mice

Identifying and resolving molecular complexities underlying chronic neuropathic pain is a significant challenge. Among the numerous classes of histone deacetylases, Class I (HDAC 1–3) and Class III (sirtuins) have been best studied in experimental pain models where inhibitor pre-treatments but not post-treatments abrogate the development of pain-related behaviors. Post-treatment here in week 3 with less well-studied Class IIa HDAC4/5 selective inhibitor LMK235 diminishes the trigeminal ganglia increases of HDAC5 RNA and protein in two chronic orofacial neuropathic pain models to levels measured in naïve mice at week 10 post-model induction. HDAC4 RNA reported in lower limb inflammatory pain models is not evident in the trigeminal models. Many other gene alterations persisting at week 10 in the trigeminal ganglia (TG) are restored to naïve levels in mice treated with LMK235. Important pain-related upregulated genes Hoxc8,b9,d8; P2rx4, Cckbr, growth hormone (Gh), and schlafen (Slfn4) are greatly reduced in LMK235-treated mice. Fold increase in axon regeneration/repair genes Sostdc1, TTr, and Folr1 after injury are doubled by LMK235 treatment. LMK235 reduces the excitability of trigeminal ganglia neurons in culture isolated from nerve injured mice compared to vehicle-treated controls, with no effect on neurons from naïve mice. Electrophysiological characterization profile includes a shift where ∼20% of the small neurons recorded under LMK235-treated conditions are high threshold, whereas none of the neurons under control conditions have high thresholds. LMK235 reverses long-standing mechanical and cold hypersensitivity in chronic trigeminal neuropathic pain models in males and females (5,10 mg/kg), preventing development of anxiety- and depression-like behaviors. PerspectiveData here support HDAC5 as key epigenetic factor in chronic trigeminal neuropathic pain persistence, validated with the study of RNA alterations, TG neuronal excitability, and pain-related behaviors. HDAC5 inhibitor given in week 3 restores RNA balance at 10 weeks, while upregulation remains for response to wound healing and chronic inflammation RNAs.

The role of cannabidiol in modulating chronic neuropathic orofacial pain

Chronic neuropathic orofacial pain is an extremely debilitating disorder that poses a burden to patients as well as the economy. Although a common condition, the management and treatment for those affected remains limited. Cannabidiol is a safe, non-psychoactive compound derived from the Cannabis sativa plant, which possesses properties that can modulate pain, including anti-neuropathic, anti-nociception and anti-inflammatory capacities. Although research is limited, cannabidiol may be able to treat chronic orofacial pain in some neurological, neurovascular and idiopathic conditions. This article aims to increase awareness of cannabidiol, and its possible use for future treatment of chronic neuropathic orofacial pain. CPD/Clinical Relevance: Cannabidiol may be useful as a treatment for chronic neuropathic orofacial pain.

GLOSSOPHARYNGEAL NERVE AS A SOURCE OF OROFACIAL PAIN - DIAGNOSTIC AND THERAPEUTIC CHALLENGES.

Chronic neuropathic orofacial pain along with physical suffering can cause emotional, psychological and social difficulties, which significantly affects the quality of life of patients. Pain in the area of glossopharyngeal nerve innervation, especially chronic neuropathic, is relatively rare, but is significant because of the great suffering it causes to sufferers. It can be life threatening, due to the cardiac arrhythmia, syncope or convulsions it can cause. Drug treatment is often of limited effectiveness and can be fraught with side effects. It is necessary to look for the etiology of the underlying disease, and if possible, to take adequate causal treatment. This review article discusses the etiology, clinical features, differential diagnosis, and treatment modalities of neuropathic pain in the area of glossopharyngeal nerve innervation.

Efficacy of low-intensity laser therapy in trigeminal neuralgia: a systematic review

IntroductionTrigeminal neuralgia (TN) is a highly prevalent cranial neuropathy, recognized as one of the main chronic orofacial neuropathic pain conditions. Low-intensity laser therapy (LILT) has been proposed as an analgesic alternative for treating neuropathic orofacial pain, although studies appear to be limited, without a consensus on dose. The study aim was to describe the efficacy of LILT in TN treatment.MethodsRandomized clinical trials and controlled trials were identified in the PubMed, Scopus, Web of Science, and ScienceDirect databases for May 8, 2021. Three independent researchers reviewed titles and abstracts to determine their eligibility. Risk of bias and quality were assessed with the RoB 2 tool (Cochrane) and PEDro scale. Decreased pain was considered the main outcome, and changes in the temporomandibular joint range of motion, strength, or disability were secondary outcomes.ResultsThe search yielded 1078 articles after eliminating duplicates, reduced to 13 when applying the selection criteria. Nine articles were ascribed a low risk of bias or remained without consensus (69.23%), obtaining an average score of 6 (PEDro). Thirteen trials showed pain reduction at the end of treatment and in follow-up, although with statistical significance for 8 articles only (p < 0.005). A decrease in drug consumption and an increase in serotonin levels were observed in experimental groups, which supports the systemic analgesic effects of local and remote LILT.ConclusionsLILT is effective in reducing pain in TN. However, more research is needed to establish a referential dose consensus for TN and other neuropathic pain conditions.

Anti-nociceptive effects of ECa 233 a standardized extract of Centella asiatica (L.) Urban on chronic neuropathic orofacial pain in mice

Ethnopharmacological relevanceECa 233 is a standardized extract of Centella asiatica (L.) Urban, a herb traditionally used to treat a number of diseases including neurological disorders. Accordingly, ECa 233 showed benefits on animal models of cognitive deficits, chronic stress and Parkinson's disease. Analgesic activity of ECa 233 was shown in Tail's flick test in rodent and relieving aphthous ulcer pain in man. Moreover, acute and sub-chronic toxicity testing in rodents and pharmacokinetic study in healthy volunteers, clinical trial phase I demonstrated good safety profiles of ECa 233. Aim of the studyThis study aims to evaluate the anti-nociceptive effects of ECa 233 and its synergistic effect with gabapentin on chronic neuropathic orofacial pain after 3 weeks infraorbital nerve chronic constriction injury in mice. The peripheral and central nociceptive activities are also examined. Materials and methodsChronic neuropathic orofacial pain was induced by 3 weeks infraorbital nerve chronic constriction injury. Mice were treated with ECa 233 (30, 100 and 300 mg/kg) and gabapentin (10 mg/kg) by oral gavage starting on day 21 and going on for 14 consecutive days. Mechanical hyperalgesia and allodynia were measured on day 7, 14, 21, 28 and 35 after infraorbital nerve chronic constriction injury. At the end of the experiment, mice were observed for the sedative effect using the locomotor activity, the calcitonin gen-related peptide in trigeminal ganglion and c-fos expression in trigeminal nucleus caudalis were investigated after euthanasia. ResultsInfraorbital nerve chronic constriction injury gradually induced marked ipsilateral mechanical hyperalgesia and allodynia. The maximum hyperalgesia and allodynia response presented on day 21 and the response was remained constant until day 35. Treatment with either 300 mg/kg ECa 233 or 10 mg/kg gabapentin were able to attenuate mechanical hyperalgesia and allodynia. The downregulation of calcitonin gen-related peptide on ipsilateral trigeminal ganglion were observed in ECa 233 at 100 and 300 mg/kg and 10 mg/kg gabapentin-treated groups. The c-fos expression on ipsilateral trigeminal nucleus caudalis was also decreased in 300 mg/kg ECa 233 and 10 mg/kg gabapentin-treated groups. ConclusionECa 233 reduced hyperalgesia and allodynia by modulating the peripheral calcitonin gen-related peptide expression consequently alleviate the nociceptive activity in trigeminal nucleus caudalis. Further clinical trial to proof ECa 233's efficacy in neuropathic pain in man as well as possible attributable mechanism of action should be further investigated.

Neuropathic orofacial pain: Characterization of different patient groups using the ICOP first edition, in a tertiary level Orofacial Pain Clinic

To characterize patients with chronic neuropathic orofacial pain in accordance with the International Classification of Orofacial Pain (ICOP first edition) criteria. A retrospective chart review of 108 patients was conducted. The most common categories observed were trigeminal neuralgia (TN) (25.9%), burning mouth syndrome (BMS) (11.1%), persistent idiopathic facial pain (PIFP) (26.9%), and posttraumatic trigeminal neuropathic pain (PTTNP) (26.9%); 9.3% of patients could not be categorized. TN and BMS was more prevalent in the sixth decade, and PIFP and PTTN were more prevalent in the fifth decade. All categories showed female predilection. The pain in TN was predominantly episodic, described as "sharp shooting" and like an "electric shock," unilateral and affecting the V2 division, and with trigger zones in 50% of patients. Pain in BMS was predominantly constant and described as "burning," with the tongue being the most common site. Pain in PIFP and PTTNP was as follows: varied from constant to episodic; described as "burning," "sharp shooting," "throbbing," or "dull aching"; intraoral or extraoral; and mostly involving the V2 or V3 division. This study is the first to characterize patients with neuropathic orofacial pain using the new ICOP criteria. PIFP and PTTNP were most commonly misdiagnosed categories. Using diagnostic criteria will increase the understanding of this patient group.

Activation of CamKII\u03b1 expressing neurons on ventrolateral periaqueductal gray improves behavioral hypersensitivity and thalamic discharge in a trigeminal neuralgia rat model

BackgroundPreceding studies have reported the association of chronic neuropathic orofacial pain with altered ongoing function in the ventrolateral periaqueductal gray (vlPAG). However, its role in trigeminal neuralgia (TN) lacks attention. We here reported the aspect that vlPAG neurons play in TN nociceptive processing by employing excitatory neuron-specific optogenetic approaches.MethodsTN was generated via unilateral infraorbital nerve chronic constriction in Sprague Dawley rats which induced mechanical and thermal pain sensitivity in air puff and acetone test, respectively. Channelrhodopsin conjugated virus with CamKIIα promoter was used to specifically activate the excitatory vlPAG neuronal population by optogenetic stimulation and in vivo microdialysis was done to determine its effect on the excitatory-inhibitory balance. In vivo extracellular recordings from ventral posteromedial (VPM) thalamus were assessed in response to vlPAG optogenetic stimulation. Depending on the experimental terms, unpaired student’s t test and two-way analysis of variance (ANOVA) were used for statistical analysis.ResultsWe observed that optogenetic activation of vlPAG subgroup neurons markedly improved pain hypersensitivity in reflexive behavior tests which was also evident on microdialysis analysis with increase glutamate concentration during stimulation period. Decreased mean firing and burst rates were evident in VPM thalamic electrophysiological recordings during the stimulation period. Overall, our results suggest the optogenetic activation of vlPAG excitatory neurons in a TN rat model has pain ameliorating effect.ConclusionsThis article presents the prospect of pain modulation in trigeminal pain pathway via optogenetic activation of vlPAG excitatory neurons in rat model. This outlook could potentially assist vlPAG insight and its optogenetic approach in trigeminal neuropathic pain which aid clinicians endeavoring towards enhanced pain relief therapy in trigeminal neuralgia patients.

Sensory, Affective, and Cognitive Effects of Trigeminal Injury in Mice

To characterize adequate study of chronic neuropathic orofacial pain induced by a mental nerve injury in a mouse model, we propose a behavioral assessment of its dimensions: sensory, affective, and cognitive. Trigeminal injury was induced by a chronic mental nerve constriction (MnC). Behavioral tests were conducted to assess the different dimensions of pain and to evaluate the general well-being of mice. Rodents who went through MnC showed signs of mechanical hyperalgesia and increased escape/avoidance behavior. They showed no alterations in general well-being behaviors, yet the injury was sufficient to induce impairment in the ability to adapt to the environmental requirements. MnC injury is an efficient model for the study of orofacial pain in mice, capable of inducing impairment in the different dimensions of pain. Intensity and temporality of its effects make our model less aggressive, yet effective to generate cognitive impairment. This work provides a solid foundation for the study of the neural circuits involved in the processing of neuropathic orofacial pain.

Motor cortex stimulation in chronic neuropathic orofacial pain syndromes: a systematic review and meta-analysis

Invasive motor Cortex Stimulation (iMCS) was introduced in the 1990’s for the treatment of chronic neuropathic orofacial pain (CNOP), although its effectiveness remains doubtful. However, CNOP is known to be a heterogeneous group of orofacial pain disorders, which can lead to different responses to iMCS. Therefore, this paper investigated (1) whether the effectiveness of iMCS is significantly different among different CNOP disorders and (2) whether other confounding factors can be impacting iMCS results in CNOP. A systematic review and meta-analysis using a linear mixed-model was performed. Twenty-three papers were included, totaling 140 CNOP patients. Heterogeneity of the studies showed to be 55.8%. A visual analogue scale (VAS) measured median pain relief of 66.5% (ranging from 0–100%) was found. Linear mixed-model analysis showed that patients suffering from trigeminal neuralgia responded significantly more favorable to iMCS than patients suffering from dysfunctional pain syndromes (p = 0.030). Also, patients suffering from CNOP caused by (supra)nuclear lesions responded marginally significantly better to iMCS than patients suffering from CNOP due to trigeminal nerve lesions (p = 0.049). No other confounding factors were elucidated. This meta-analysis showed that patients suffering from trigeminal neuralgia and patients suffering from (supra)nuclear lesions causing CNOP responded significantly more favorable than others on iMCS. No other confounding factors were found relevant.

Orofacial Antinociceptive Effect of Nifedipine in Rodents Is Mediated by TRPM3, TRPA1, and NMDA Processes.

To test for the possible antinociceptive effect of nifedipine in rodent models of acute and chronic neuropathic orofacial pain and the possible involvement of TRP- and NMDA-related processes in this effect. Acute nociceptive behavior was induced by administering formalin, cinnamaldehyde, glutamate, capsaicin, or acidified saline to the upper lip or hypertonic saline to the cornea of Swiss mice. Acute nociceptive behavior was also induced by formalin injected into the TMJ or mustard oil injected into the masseter muscle of Wistar rats. The chronic pain model involved infraorbital nerve transection (IONX) in Wistar rats to induce mechanical hypersensitivity, which was assessed with von Frey hair stimulation of the upper lip. The effects of pretreatment with nifedipine or vehicle (control) were tested on the nociceptive behaviors. Docking experiments were also performed. Statistical analysis included one-way ANOVA followed by Tukey post hoc test and two-way ANOVA followed by Bonferroni post hoc test (statistical significance P < .05). Nifedipine produced significant antinociceptive effects in all of the acute nociceptive behaviors except that induced by capsaicin. The antinociceptive effects were attenuated by NMDA, TRPA1, or TRPM3 receptor antagonists. The IONX animals developed facial mechanical hypersensitivity, which was significantly reduced by nifedipine. The docking experiments suggested that nifedipine may interact with TRPM3 and NMDA receptors. The present study has provided novel findings in a variety of acute and chronic orofacial pain models showing that nifedipine, a selective inhibitor of L-type Ca2+ channels, can suppress orofacial nociceptive behavior through NMDA, TRPA1, and TRPM3 receptor systems.

Differential Diagnosis of Chronic Neuropathic Orofacial Pain: Role of Clinical Neurophysiology.

Orofacial pain syndromes encompass several clinically defined and classified entities. The focus here is on the role of clinical neurophysiologic and psychophysical tests in the diagnosis, differential diagnosis, and pathophysiological mechanisms of definite trigeminal neuropathic pain and other chronic orofacial pain conditions (excluding headache and temporomandibular disorders). The International Classification of Headache Disorders 2018 classifies these facial pain disorders under the heading Painful cranial neuropathies and other facial pains. In addition to unambiguous painful posttraumatic or postherpetic trigeminal neuropathies, burning mouth syndrome, persistent idiopathic facial and dental pain, and trigeminal neuralgia have also been identified with neurophysiologic and quantitative sensory testing to involve the nervous system. Despite normal clinical examination, these all include clusters of patients with evidence for either peripheral or central nervous system pathology compatible with the subclinical end of a continuum of trigeminal neuropathic pain conditions. Useful tests in the diagnostic process include electroneuromyography with specific needle, neurography techniques for the inferior alveolar and infraorbital nerves, brain stem reflex recordings (blink reflex with stimulation of the supraorbital, infraorbital, mental, and lingual nerves; jaw jerk; masseter silent period), evoked potential recordings, and quantitative sensory testing. Habituation of the blink reflex and evoked potential responses to repeated stimuli evaluate top-down inhibition, and navigated transcranial magnetic stimulation allows the mapping of reorganization within the motor cortex in chronic neuropathic pain. With systematic use of neurophysiologic and quantitative sensory testing, many of the current ambiguities in the diagnosis, classification, and understanding of chronic orofacial syndromes can be clarified for clinical practice and future research.

Effects of the glial modulator palmitoylethanolamide on chronic pain intensity and brain function.

Background: Chronic neuropathic pain (NP) is a complex disease that results from damage or presumed damage to the somatosensory nervous system. Current treatment regimens are often ineffective. The major impediment in developing effective treatments is our limited understanding of the underlying mechanisms. Preclinical evidence suggests that glial changes are crucial for the development of NP and a recent study reported oscillatory activity differences within the ascending pain pathway at frequencies similar to that of cyclic gliotransmission in NP. Furthermore, there is evidence that glial modifying medications may be effective in treating NP. The aim of this Phase I open-label clinical trial is to determine whether glial modifying medication palmitoylethanolamide (PEA) will reduce NP and whether this is associated with reductions in oscillatory activity within the pain pathway.Methods: We investigated whether 6 weeks of PEA treatment would reduce pain and infra-slow oscillatory activity within the ascending trigeminal pathway in 22 individuals (17 females) with chronic orofacial NP.Results: PEA reduced pain in 16 (73%) of the 22 subjects, 11 subjects showed pain reduction of over 20%. Whilst both the responders and non-responders showed reductions in infra-slow oscillatory activity where orofacial nociceptor afferents terminate in the brainstem, only responders displayed reductions in the thalamus. Furthermore, functional connections between the brainstem and thalamus were altered only in responders.Conclusion: PEA is effective at relieving NP. This reduction is coupled to a reduction in resting oscillations along the ascending pain pathway that are likely driven by rhythmic astrocytic gliotransmission.

Mental nerve injury induces novelty seeking behaviour leading to increasing ethanol intake in Wistar rats

ObjectiveDental treatment and orofacial surgeries may induce chronic neuropathic orofacial pain (CNOP). This kind of pain affects adaptability to environmental changes in both model animals and humans. Part of the adaptation process depends on the ability to distinguish between familiar and novel stimuli. CNOP induces novelty seeking behaviour as a deficit in environmental adaptation. Alternatively, novelty seeking is a sign for susceptibility to the development of substance abuse. Evidence shows that CNOP leads to alcoholism in animal models. The behavioural relationship between CNOP, novelty seeking behaviour and substance abuse is unknown. In this article, we investigate if CNOP produces an increase in novelty seeking and leads to increasing ethanol intake. DesignFirstly, we used mental nerve injury as a neuropathic orofacial pain model to evaluate both thermal and mechanical allodynia. We used the novel recognition task to determine novelty seeking behaviour and the drink in darkness protocol to assess ethanol intake. ResultsOur results show that mental nerve constriction increases novelty seeking behaviour (p = 0.01) and correlates with ethanol binge consumption (r2 = 0.68, p = 0.0008). ConclusionsThe present study demonstrates, for the first time, that trigeminal nerve injury, which induces CNOP, is enough to provide novelty seeking behaviour and lead to increasing ethanol intake. The increase of novelty seeking behaviour can serve as a predictor of risk of developing substance abuse. The treatment of CNOP involves a high risk of producing addiction. The level of novelty seeking evaluation in patients with neuropathic pain before treatment is critical.

Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury.

The study aim was to determine how peripheral trigeminal nerve injury affects mitochondrial respiration and to test efficacy of combined treatment with 2 Federal Drug Administration approved drugs with potential for improving mitochondrial bioenergetics, pain and anxiety-related behaviors in a chronic orofacial neuropathic pain mouse model. Efficacy of (R)-(+)-4-amino-3-isoxazolidinone (D-cycloserine, DCS), an N-Methyl-D-aspartate antagonist/agonist, and Pioglitazone (PIO), a selective agonist of nuclear receptor peroxisome proliferator-activated receptor gamma was investigate in the trigeminal inflammatory compression (TIC) neuropathic nerve injury mouse model. Combined low doses of these drugs (80 mg/kg DCS and 100 mg/kg PIO) were given as a single bolus or daily for 7 days post-TIC to test ability to attenuate neuropathic nociceptive and associated cognitive dependent anxiety behaviors. In addition, beneficial effects of the DCS/PIO drug combination were explored ex vivo in isolated cortex/brainstem mitochondria at 28 weeks post-TIC. The DCS/PIO combination not only attenuated orofacial neuropathic pain and anxiety-related behaviors associated with trigeminal nerve injury, but it also improved mitochondrial bioenergetics. The DCS/PIO combination uncoupled mitochondrial respiration in the TIC model to improve cortical mitochondrial dysfunction, as well as reduced nociceptive and anxiety behaviors present in mice with centralized chronic neuropathic nerve injury. Combining these drugs could be a beneficial treatment for patients with depression, anxiety, or other psychological conditions due to their chronic pain status.

The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain.

Recurrent thalamocortical connections are integral to the generation of brain rhythms and it is thought that the inhibitory action of the thalamic reticular nucleus is critical in setting these rhythms. Our work and others' has suggested that chronic pain that develops following nerve injury, that is, neuropathic pain, results from altered thalamocortical rhythm, although whether this dysrhythmia is associated with thalamic inhibitory function remains unknown. In this investigation, we used electroencephalography and magnetic resonance spectroscopy to investigate cortical power and thalamic GABAergic concentration in 20 patients with neuropathic pain and 20 pain-free controls. First, we found thalamocortical dysrhythmia in chronic orofacial neuropathic pain; patients displayed greater power than controls over the 4-25 Hz frequency range, most marked in the theta and low alpha bands. Furthermore, sensorimotor cortex displayed a strong positive correlation between cortical power and pain intensity. Interestingly, we found no difference in thalamic GABA concentration between pain subjects and control subjects. However, we demonstrated significant linear relationships between thalamic GABA concentration and enhanced cortical power in pain subjects but not controls. Whilst the difference in relationship between thalamic GABA concentration and resting brain rhythm between chronic pain and control subjects does not prove a cause and effect link, it is consistent with a role for thalamic inhibitory neurotransmitter release, possibly from the thalamic reticular nucleus, in altered brain rhythms in individuals with chronic neuropathic pain.

Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain.

The neural mechanisms underlying the development and maintenance of chronic pain following nerve injury remain unclear. There is growing evidence that chronic neuropathic pain is associated with altered thalamic firing patterns, thalamocortical dysrhythmia and altered infra-slow oscillations in ascending pain pathways. Preclinical and post-mortem human studies have revealed that neuropathic pain is associated with prolonged astrocyte activation in the dorsal horn and we have suggested that this may result in altered gliotransmission, which results in altered resting neural rhythm in the ascending pain pathway. Evidence of astrocyte activation above the level of the dorsal horn in living humans is lacking and direct measurement of astrocyte activation in living humans is not possible, however, there is evidence that regional alterations in T2 relaxation times are indicative of astrogliosis. The aim of this study was to use T2 relaxometry to explore regional brain anatomy of the ascending pain pathway in individuals with chronic orofacial neuropathic pain. We found that in individuals with trigeminal neuropathic pain, decreases in T2 relaxation times occurred in the region of the spinal trigeminal nucleus and primary somatosensory cortex, as well as in higher order processing regions such as the dorsolateral prefrontal, cingulate and hippocampal/parahippocampal cortices. We speculate that these regional changes in T2 relaxation times reflect prolonged astrocyte activation, which results in altered brain rhythm and ultimately the constant perception of pain. Blocking prolonged astrocyte activation may be effective in preventing and even reversing the development of chronic pain following neural injury.

Brainstem Pain-Control Circuitry Connectivity in Chronic Neuropathic Pain.

Preclinical investigations have suggested that altered functioning of brainstem pain-modulation circuits may be crucial for the maintenance of some chronic pain conditions. While some human psychophysical studies show that patients with chronic pain display altered pain-modulation efficacy, it remains unknown whether brainstem pain-modulation circuits are altered in individuals with chronic pain. The aim of the present investigation was to determine whether, in humans, chronic pain following nerve injury is associated with altered ongoing functioning of the brainstem descending modulation systems. Using resting-state functional magnetic resonance imaging, we found that male and female patients with chronic neuropathic orofacial pain show increased functional connectivity between the rostral ventromedial medulla (RVM) and other brainstem pain-modulatory regions, including the ventrolateral periaqueductal gray (vlPAG) and locus ceruleus (LC). We also identified an increase in RVM functional connectivity with the region that receives orofacial nociceptor afferents, the spinal trigeminal nucleus. In addition, the vlPAG and LC displayed increased functional connectivity strengths with higher brain regions, including the hippocampus, nucleus accumbens, and anterior cingulate cortex, in individuals with chronic pain. These data reveal that chronic pain is associated with altered ongoing functioning within the endogenous pain-modulation network. These changes may underlie enhanced descending facilitation of processing at the primary synapse, resulting in increased nociceptive transmission to higher brain centers. Further, our findings show that higher brain regions interact with the brainstem modulation system differently in chronic pain, possibly reflecting top-down engagement of the circuitry alongside altered reward processing in pain conditions.SIGNIFICANCE STATEMENT Experimental animal models and human psychophysical studies suggest that altered functioning of brainstem pain-modulation systems contributes to the maintenance of chronic pain. However, the function of this circuitry has not yet been explored in humans with chronic pain. In this study, we report that individuals with orofacial neuropathic pain show altered functional connectivity between regions within the brainstem pain-modulation network. We suggest that these changes reflect largely central mechanisms that feed back onto the primary nociceptive synapse and enhance the transfer of noxious information to higher brain regions, thus contributing to the constant perception of pain. Identifying the mechanisms responsible for the maintenance of neuropathic pain is imperative for the development of more efficacious therapies.

The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders.

Background:Mechanisms underlying alleviation of neuropathic pain by repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) and right secondary somatosensory cortex (S2) are only partly known. Patients with chronic neuropathic pain often have comorbidities like depression and sleep problems. Through functional connectivity, rTMS of M1 and S2 may activate dorsolateral prefrontal cortex, the target for treating depression with rTMS. Thus, the analgesic effect of rTMS could be mediated indirectly via improvement of psychiatric comorbidities or sleep. We examined whether rTMS has an independent analgesic effect or whether its clinical benefits depend on effects on mood or sleep. We also evaluated if comorbid psychiatric or sleep disorders predict the treatment outcome.Methods:Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized controlled crossover rTMS study. Patients’ psychiatric history was evaluated by a specialist in psychiatry. Intensity and interference of pain, mood, and the quality of sleep and life were evaluated at baseline and after 2 active (primary somatosensory cortex [S1]/M1 and S2) and placebo rTMS treatments. A logistic regression analysis was done to investigate predictors of treatment outcome.Results:The analgesic effect of the right S2 stimulation was not associated with improvement of psychiatric conditions or sleep, whereas S1/M1 stimulation improved sleep without significant analgesic effect (P = 0.013–0.046 in sleep scores). Psychiatric and sleep disorders were more common in patients than in the general population (P = 0.000–0.001 in sleep scores), but these comorbidities did not predict the rTMS treatment outcome.Conclusion:We conclude that rTMS to the right S2 does not exert its beneficial analgesic effects in chronic neuropathic orofacial pain via indirect improvement of comorbid psychiatric or sleep disorders.

Orofacial Neuropathic Pain Leads to a Hyporesponsive Barrel Cortex with Enhanced Structural Synaptic Plasticity.

Chronic pain is a long-lasting debilitating condition that is particularly difficult to treat due to the lack of identified underlying mechanisms. Although several key contributing processes have been described at the level of the spinal cord, very few studies have investigated the supraspinal mechanisms underlying chronic pain. Using a combination of approaches (cortical intrinsic imaging, immunohistochemical and behavioural analysis), our study aimed to decipher the nature of functional and structural changes in a mouse model of orofacial neuropathic pain, focusing on cortical areas involved in various pain components. Our results show that chronic neuropathic orofacial pain is associated with decreased haemodynamic responsiveness to whisker stimulation in the barrel field cortex. This reduced functional activation is likely due to the increased basal neuronal activity (measured indirectly using cFos and phospho-ERK immunoreactivity) observed in several cortical areas, including the contralateral barrel field, motor and cingulate cortices. In the same animals, immunohistochemical analysis of markers for active pre- or postsynaptic elements (Piccolo and phospho-Cofilin, respectively) revealed an increased immunofluorescence in deep cortical layers of the contralateral barrel field, motor and cingulate cortices. These results suggest that long-lasting orofacial neuropathic pain is associated with exacerbated neuronal activity and synaptic plasticity at the cortical level.

GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC’s relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABAA receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABAA signaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABAA-mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator.