Effectiveness of photobiomodulation and orofacial myofunctional therapy in orofacial pain disorders. A systematic review of randomized control trials.

Orofacial pain can significantly affect physical, psychological, and overall quality of life. This study aimed to compare the effectiveness of combining photobiomodulation (PBM) with orofacial myofunctional therapy (OMT) in managing orofacial pain disorders. An electronic search of randomized controlled trials in electronic databases was performed until March 2024. Randomized controlled trials (RCTs) focusing on PBM and OMT for the management of orofacial pain were included. Risk of bias across individual studies was performed using the Cochrane risk of bias tool for interventions. A total of 10 RCTs were included, out of which 7 RCTs revealed that the combined approach of PBM and OMT had a more pronounced impact on diminishing pain and enhancing functional activity in patients with orofacial disorders. One study reported significant increases in pressure pain threshold for TMJ, masseter, and anterior temporalis muscles at both sides in the post-treatment compared with the pre-treatment in both groups. The risk of bias was low in 7, moderate in 2, and high in 1 study. The efficacy of a combined modality treatment of PBM with OMT for orofacial pain disorder shows promising results. However, further randomized controlled trials with extended follow-up periods standardized PBM and OMT parameters are warranted to obtain firm conclusions.

Effectiveness of mineral trioxide aggregate on postoperative pain in non-surgical endodontic treatment: a systematic review of randomized controlled trials.

INTRODUCTION: Postoperative endodontic pain can negatively influence the quality of life of the patients. Mineral Trioxide Aggregate (MTA) has gained attention as a potential medicament in various endodontic procedures. MTA has been shown to have desirable properties such as biocompatibility, marginal adaptation, and sealing ability compared to other materials. Limited evidence is available about the effectiveness of MTA on the reduction of postoperative pain following endodontic treatment. This article aimed to compare the non-surgical post-endodontic pain-relieving effect of MTA compared with other materials. METHODS: Indexed databases (PubMed/Medline, EMBASE, OVID, Scopus, and Cochrane) were independently searched for relevant manuscripts published up to and until June 2023. Randomized controlled trials (RCTs) with a focus on teeth with pulp pathologies, with or without radiolucency, requiring primary endodontic treatment were included. Risk of bias across individual studies was performed using the Cochrane risk of bias tool for interventions. RESULTS: Out of the initial 169 articles searched, 9 RCTs met the selection criteria. The protocols were like all the studies, but the pain rating scales, filling material, and restoration materials varied. Out of the 9 included studies, in 4 studies MTA significantly reduced postoperative pain levels, 5 studies showed no difference between MTA and other materials, whereas 1 study reported an adverse effect of grey discoloration after MTA. CONCLUSION: The findings of the present review indicate that MTA may reduce postoperative pain following non-surgical endodontic treatment. However, future standardized studies should be conducted to validate the results.

Genetic variation in catechol-O-methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects.

BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

Exercise induced hypoalgesia profile in rats is associated with IL-10 and IL-1 ß levels and pain severity following nerve injury.

BACKGROUND: Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. METHODS: Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. RESULTS: The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. CONCLUSION: EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.

Molecular mechanisms of painful traumatic trigeminal neuropathy-Evidence from animal research and clinical correlates.

Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.

Dental management of patients with congestive heart failure before and after implantation of ventricular assist devices: linking the missing protocol.

Objectives: There are no studies that have reviewed the pre- and post-operative dental protocols for the management of congestive heart failure (CHF) patients before and after implantation of the left ventricular assist device (LVAD). The aim of the present study was to review the pre- and post-operative dental protocols reported in indexed literature related to the management of CHF patients before and after implantation of ventricular assist devices (VAD). Design: The addressed focused question was "Is there a protocol for the dental management of end-stage CHF patients before and after VAD implantation?" Indexed databases were searched using various keywords. Letters to the Editor, review articles, and commentaries/expert opinions were excluded. Results: Seven studies were included and processed for data extraction. The number of participants ranged between 1 and 32 individuals, with age ranging between 14 and 66 years. Dental extractions were performed in 5 studies, and in 2 studies scaling and root planing was done for the treatment of periodontal diseases. One study assessed odontogenic infective foci and other lesions of the oral soft and hard tissues as a preoperative protocol. Six of the 7 studies did not report a dental therapeutic protocol, which was followed for the pre and/or post-LVAD implantation. Conclusions: It is recommended that standardized protocols should be adopted that allow the delivery of safe and effective pre- and postoperative dental care to VAD patients. Such protocols may help influence the morbidity and mortality rates and simultaneously improve the overall quality of life in vulnerable patients.

Altered pain modulation to noxious heat thermal stimuli in burning mouth syndrome.

OBJECTIVES: The aim of this study was to examine temporal summation (TS) and conditioned pain modulation (CPM) in patients with burning mouth syndrome (BMS) and healthy controls using intra-epidermal electrical stimulation (IES). MATERIALS AND METHODS: Twenty-six female patients with BMS and 27 healthy female controls participated in this study. A single stimulus with electrical stimulation followed by a train of 10 successive stimuli was administered to the right chin of participants in both the BMS and control groups. CPM was evaluated with the changes of TS calculated from the difference in numerical pain scale data between these two test stimuli and the following warm (40°C) and hot (47°C) conditioning stimuli applied at the non-dominant hand in both the BMS and control groups. RESULTS: TS was present in both the BMS and control groups. CPM in the BMS group was significantly less efficient at the 47°C condition than that in the control group, while no significant difference was observed in the CPM between the BMS and the control groups at the 40°C condition. CONCLUSION: These findings indicate that BMS is associated with a deficit inhibitory CPM and implicate the involvement of the central nervous system in the pathophysiology of BMS.

Acute and chronic pain in orofacial trauma patients.

Trauma or injury to the dentition and supporting tissues is associated with pain and discomfort, as expected, that may present immediately, shortly afterwards, or within a few days. Pain is an essential response to injury because it allows the organism to develop avoidance behavior to potential threats and helps the organism to avoid usage of the injured organ during the healing process. Not only does external trauma induce pain, but also essential invasive dental procedures such as extractions, dental implant insertions, root canal treatments, and oral surgeries are accompanied by similar post-surgical (post-traumatic) pain. The pain intensity after trauma varies and does not always correlate with the extent of injury. Trauma to the orofacial region or the teeth may also indirectly affect and induce pain in other orofacial structures such as the masticatory muscles, the temporomandibular joint, and even the cervical spine. In most cases, the pain will resolve as soon as healing of the affected tissue occurs or after dental and routine palliative treatment. In a limited number of cases, the pain persists beyond healing and evolves into a chronic pain state. Chronic pain in the orofacial region presents diagnostic and management challenges. Misdiagnosis or delayed diagnosis of the oral chronic pain condition may lead to unnecessary dental treatment. This article will discuss diagnosis and treatment for acute and chronic pain as well as potential mechanisms involved in the undesirable transition from acute to chronic pain.

Influence of increased body mass index on orthodontic tooth movement and related parameters in children and adolescents: A systematic review of longitudinal controlled clinical studies.

OBJECTIVES: To assess the impact of increased body mass index (BMI) on orthodontic tooth movement (OTM) and related parameters in children and adolescents. SEARCH SOURCES: A search of six electronic databases and manual searching were performed up to June 2019 without language and time restrictions. DATA SELECTION: Eligibility criteria were as follows: (1) longitudinal controlled clinical studies; (2) children and adolescents undergoing orthodontic therapy (OT); (3) no systemic diseases; (4) experimental group: patients with increased BMI; and (5) control group: patients with normal BMI. DATA EXTRACTION: Screening, study selection and data extraction were performed; bias within studies was assessed using the Risk of Bias In Non-randomised Studies (ROBINS-I) tool. RESULTS: Seven studies were included. One study showed that an increased BMI is associated with less wear-time of removable orthodontic appliances and one study found no significant association. One study showed that an increased BMI is associated with less cooperation during OT; however, not with the treatment results. One study reported higher pain experience during OT in adolescents with than without increased BMI. Two studies showed that increased BMI in adolescents is related to OTM, one with increased and one with decreased rates of OTM, respectively. One study reported an association between increased BMI and incidence of white spot lesions and gingivitis during OT. The ROBINS-I tool showed low to moderate risk of bias within studies. CONCLUSIONS: The influence of BMI on OTM and related parameters in children and adolescents remains debatable.

Effect of Pregabalin and Diclofenac on tactile allodynia, mechanical hyperalgesia and pro inflammatory cytokine levels (IL-6, IL-1ß) induced by chronic constriction injury of the infraorbital nerve in rats.

The present study evaluated the effects of systemic pregabalin (PG) and diclofenac (Dic) on neuropathic orofacial pain induced by chronic constriction injury (CCI) of the infraorbital nerve (ION) and on the pro-inflammatory cytokines levels in the affected nerve. Fifty-four rats underwent left infra orbital nerve CCI, and 7 days after the procedure as the pain developed, the rats were randomly assigned to one of the treatment groups: PG 300, 30 or 10 mg/kg, Dic 10, 5 or 1 mg/kg or saline group (Sal) (n/group = 8). Addiitonal 8 rats served as naïve control group. Tactile-allodynia and Mechano-hyperalgesia were tested before the surgical procedure and at days 7, 8, and 9 postoperatively. On the 9th day, the rats were euthanized and the affected and contralateral sciatic nerves were harvested to assess IL-6 and IL-1ß nerve levels employing enzyme linked immunosorbent assay (ELISA). Daily injection of PG (all doses) significantly reduced tactile-allodynia and mechano-hyperalgesia (p < .05) while Dic did not. On the 9th day, the ipsilateral nerve IL-6 levels were significantly decreased (p < .05) in the PG and DIC groups compared to the Sal group. IL-1ß levels demonstrated a significant reduction (p < .05) in the PG group when compared to saline. These results suggest that PG but not Dic may be effective in reducing neuropathic orofacial pain. The mechanisms of action may be associated to some extent with reduction in IL-1ß levels in the affected nerve.

Presentation of cysticercosis of the lateral pterygoid muscle as temporomandibular disorder: A diagnostic and therapeutic challenge.

Orofacial pain can often be the chief complaint of many systemic disorders. Cysticercosis involving the lateral pterygoids may cause limitation of mouth opening and may mimic clinical symptoms of a temporomandibular disorder. A 37-year-old female presented with 1-month-old complaint of limited mandibular range of motion. She reported a similar episode a year earlier and was diagnosed with a temporomandibular joint disorder by her primary dentist. Comprehensive intra- and extra-oral examinations were performed, which revealed a limitation of mouth opening accompanied by mild limitation of contralateral excursion. A magnetic resonance imaging revealed a ring-enhancing lesion within the left pterygoid muscle suggestive of cysticercosis. The patient was referred to her primary care physician for further treatment and given physical therapy (stretching exercises) to improve mouth opening. One week later, she developed lesions in the arm and trunk. Further ultrasound imaging of the abdomen and the forearms confirmed the diagnosis of cysticercosis. She was treated with albendazole, physiotherapy, joint stabilization appliance, and had eventual complete recovery. This case emphasizes the importance of diagnosis of a systemic condition that may have serious implications, if untreated, and the importance of a comprehensive evaluation, workup, and multidisciplinary management.

Pro and anti-inflammatory cytokine levels (TNF-α, IL-1ß, IL-6 and IL-10) in rat model of neuroma.

Traumatic neuroma is neuronal tissue proliferation developed in a nerve injury site, often associated with increased sensitivity and spontaneous or evoked neuropathic pain. The mechanisms leading to the disorganized nerve proliferation are not completely understood, though inflammation in the injured nerve vicinity most likely has a role in the process. Inflammatory cytokines are also known to be involved in the maintenance and development of post-traumatic and neuropathic pain. The goal of this study was to quantify and compare pro and anti-inflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-10) levels in nerves that formed neuromas and nerves that did not, following sciatic nerve transection. A total of 30 rats were used in this study. Twenty rats underwent sciatic nerve transection and 10 underwent sham surgery. Six weeks post-surgery nerve sections were collected and histologically evaluated for neuroma formation. The samples were then classified as neuroma, non-neuroma and sham groups. TNF-α, IL-1ß, IL-6 and IL-10 levels were measured in the nerves employing ELISA. TNF-α levels were significantly higher in both neuroma and non-neuroma-forming injured nerves compared to the sham group. IL-1ß and IL-6 levels were significantly higher in the neuroma-forming nerves compared to the sham group. IL-10 levels were significantly higher in the non-neuroma group compared to the sham group. In conclusion IL-6, and IL-1 ß may have a role in the formation of traumatic neuroma while IL-10 may inhibit neuroma formation.

Role of Collagen Conduit With Duloxetine and/or Pregabalin in the Management of Partial Peripheral Nerve Injury.

PURPOSE: The objective of this study was to investigate the analgesic effect of a collagen conduit (Neuragen, Integra LifeSciences Corp, Plainsboro, NJ) using duloxetine (Cymbalta, Lilly, Indianapolis, IN) with or without pregabalin (Lyrica, Pfizer, NY) on pain induced by partial sciatic nerve transection in a rat model. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were divided into 5 groups (n = 10 per group): group 1, nerve damage with no treatment; group 2, nerve damage treated with the application of a collagen conduit and saline; group 3, nerve damage treated with the application of a collagen conduit and duloxetine; group 4, nerve damage treated with the application of a collagen conduit and pregabalin; and group 5, nerve damage treated with the application of a collagen conduit and pregabalin plus duloxetine. Pain levels were evaluated by responses to mechanical and thermal stimuli at baseline before and 3 and 7 days after surgery. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF) levels were evaluated in blood, sciatic nerve, and dorsal root ganglion samples collected 7 days after surgery. RESULTS: The group treated with the collagen conduit and pregabalin exhibited markedly less pain 7 days postoperatively in response to mechanical and thermal stimuli compared with the other groups. IL-10 levels were considerably increased in the group treated with pregabalin. The groups treated with a collagen conduit and duloxetine and a combination of pregabalin and duloxetine also exhibited markedly less pain in response to mechanical and thermal stimuli 7 days after surgery compared with the group that had only nerve injury. The decrease in pain using duloxetine was not as robust but was associated with a decrease of TNF-α. The combination of pregabalin and duloxetine resulted in a substantial decrease in IL-6. CONCLUSION: Using a collagen conduit and duloxetine, pregabalin, and their combination helped alleviate neuropathic pain. The mechanism of action might be associated, at least in part, to cytokines.

Efficacy of regional nerve block in management of myofascial pain of masseteric origin.

OBJECTIVE: To compare the efficacy of a regional masseteric nerve block (MNB) in the management of myofascial pain of masseteric origin, relative to trigger point injection (TrP-Inj) and intra-oral stabilization appliance (IOA). STUDY DESIGN: A retrospective chart review of 200 patients treated for myofascial pain of masseteric origin was performed. Sixty patients met the eligibility criteria and were grouped based on their treatment regimen; IOA, TrP-Inj or MNB. Pain scores recorded at pre-treatment (baseline), 30 minutes post-treatment, and 2 weeks post-treatment were analyzed. RESULTS: Treatment with MNB resulted in significant reduction in pain at 30 minutes and two weeks post-treatment compared to TrP-Inj and IOA. CONCLUSION: MNB provided an immediate and sustained therapeutic effect for the management of myofascial pain for at least up to two weeks. MNB is a simple and valuable tool in the management of myogenous pain, especially for the non-orofacial pain practitioner.

Lymphoma masquerading as jaw pain, headache, and syncope: A case report.

BACKGROUND: Lymphomas of parapharyngeal space often have complex manifestations, posing a diagnostic dilemma for clinicians. CASE DESCRIPTION: A 64-year-old man sought treatment for a 4-month history of unresolving right-sided headache and jaw pain associated with syncope, all of which started with a toothache. Since the onset of pain, the patient had undergone multiple diagnostic tests with various specialists, with no pain relief. A detailed clinical and radiologic examination by an orofacial pain specialist revealed diffuse large B-cell lymphoma in the parapharynx. PRACTICAL IMPLICATIONS: A thorough knowledge of the head and neck anatomy helps in identifying the pathophysiology of complex orofacial pain manifestations, which assists in early diagnosis and treatment.

The efficacy of photobiomodulation on dental injection pain: a systematic review of randomized clinical trials.

Dental injections are routinely performed and can result in pain and anxiety in patients. This systematic review aimed to evaluate the efficacy of photobiomodulation therapy (PBMT) in dental injections for pain management in patients undergoing dental treatment. Indexed databases, including PubMed, EMBASE, Scopus, ISI Web of Knowledge, and Cochrane Library, were electronically searched without a time limit up to February 2024. A risk of bias evaluation was performed using the Cochrane tool. A preliminary investigation using electronic and manual methods yielded 4,920,881 manuscripts. Based on the eligibility requirements, 13 randomized control trials (RCTs) were included. Self-assessed pain was determined using the visual analog scale, Face, Legs, Activity, Cry, Controllability scale, or Wong-Baker face pain scale. Eight RCTs demonstrated a notable decrease in needle pain in patients undergoing dental needle injections using PBMT. Based on current evidence, PBMT may help reduce needle pain related to dental anesthesia. Further standardized studies are needed to assess the significance of PBMT for postoperative pain in patients undergoing dental injections.

Effect of Lithium on Orthodontic Tooth Movement: a Systematic Review of Animal Studies.

Objective: This study aimed to systematically review the effect of lithium on orthodontic tooth movement (OTM). Methods: The focus question was "does lithium have an effect on OTM?" A systematic search was conducted using indexed databases and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The quality assessment of the selected studies was performed according to the systematic review center for laboratory animal experimentation. Results: Five of the initially identified 656 articles fulfilled the eligibility criteria and were selected for this review. The studies reported that lithium administration lowered the rate of OTM by inducing a reduction in the number of osteoclasts and possibly inhibiting osteoclastogenesis. These studies further showed an increase in bone density and bone volume by promoting the Wnt/ß-catenin signaling pathway and osteoblastogenesis. It was also noted that lithium reduced orthodontically induced root resorption during experimental OTM. Further, standardized studies are warranted to understand the impact of lithium in OTM. Overall, the risk of bias for 3 studies was very high, high in 1 study, and moderate in 1 study. Conclusion: On an experimental level in animals, lithium decreased the rate of OTM during the active treatment phase by increasing bone density and bone volume and reducing root resorption. In addition, lithium may enhance alveolar bone formation during orthodontic retention. Clinically, this may impact the orthodontic treatment duration in patients receiving lithium, and further studies are needed to understand the true impact of lithium on OTM.

Time-Course Progression of Whole Transcriptome Expression Changes of Trigeminal Ganglia Compared to Dorsal Root Ganglia in Rats Exposed to Nerve Injury.

Mechanisms underlying neuropathic pain (NP) are complex with multiple genes, their interactions, environmental and epigenetic factors being implicated. Transcriptional changes in the trigeminal (TG) and dorsal root (DRG) ganglia have been implicated in the development and maintenance of NP. Despite efforts to unravel molecular mechanisms of NP, many remain unknown. Also, most of the studies focused on the spinal system. Although the spinal and trigeminal systems share some of the molecular mechanisms, differences exist. We used RNA-sequencing technology to identify differentially expressed genes (DEGs) in the TG and DRG at baseline and 3 time points following the infraorbital or sciatic nerve injuries, respectively. Pathway analysis and comparison analysis were performed to identify differentially expressed pathways. Additionally, upstream regulator effects were investigated in the two systems. DEG (differentially expressed genes) analyses identified 3,225 genes to be differentially expressed between TG and DRG in naïve animals, 1,828 genes 4 days post injury, 5,644 at day 8 and 9,777 DEGs at 21 days postinjury. A comparison of top enriched canonical pathways revealed that a number of signaling pathway was significantly inhibited in the TG and activated in the DRG at 21 days postinjury. Finally, CORT upstream regulator was predicted to be inhibited in the TG while expression levels of the CSF1 upstream regulator were significantly elevated in the DRG at 21 days postinjury. This study provides a basis for further in-depth studies investigating transcriptional changes, pathways, and upstream regulation in TG and DRG in rats exposed to peripheral nerve injuries. PERSPECTIVE: Although trigeminal and dorsal root ganglia are homologs of each other, they respond differently to nerve injury and therefore treatment. Activation/inhibition of number of biological pathways appear to be ganglion/system specific suggesting that different approaches might be required to successfully treat neuropathies induced by injuries in spinal and trigeminal systems.

Anti-nociceptive effect of IL-12p40 in a rat model of neuropathic pain.

IL-12p70 is a proinflammatory cytokine secreted by dendritic cells, monocytes and macrophages. It plays a crucial role in cell-mediated immunity by inducing proliferation of T cell and natural killer cells, and enhancing their cytotoxic activity. In adaptive immune response, it acts on naive T cells to differentiate into Th1-type cells. It is composed of two subunits, p35 and p40. The latter can be secreted in the form of monodimer or heterodimer, which is also referred as IL-12p80. Recently IL-12p70 has been proven to locally provoke nociceptive effect in naïve rats. This study investigated pain response following systemic administration of IL-12p70 and IL-12p40 homodimer in chronic neuropathic pain model, induced by chronic constriction injury. The doses tested were IL-12p40 homodimer or IL12p70 at 15, 150 and 1500ng/kg, respectively. Pain was assessed at 1, 4, 7 and 24h after injection, in the form of tactile allodynia and mechanical hyperalgesia. The side effect of sensory motor disability was measured by rotarod performance. By all behavioral measures, IL-12p70 of any dosage, at any time point, had no significant effect on tactile allodynia and mechanical hyperalgesia. A high dose of IL-12p40 homodimer induced significant analgesic effect by the measure of hind paw tactile allodynia from 1h to 4h after injection. Medium and low doses of IL-12p40 homodimer exerted their analgesic effect 4h post injection. Mechanical hyperalgesia, following high and medium doses of IL-12p40 administration, was significantly reduced at 4h after application. Also, no significant sensory motor dysfunction was detected for all dosage for both homodimers. These findings suggest that systemic application of IL-12p40 homodimer induces time-dependent analgesia to mechanical stimulation in rats exposed to neuropathic pain.

Placenta-derived adherent cells attenuate hyperalgesia and neuroinflammatory response associated with perineural inflammation in rats.

Neuropathic pain is a debilitating condition of the somatosensory system caused by pathology of the nervous system. Current drugs treat symptoms but largely fail to target the underlying mechanisms responsible for the pathological changes seen in the central or peripheral nervous system. We investigated the therapeutic effects of PDA-001, a culture expanded placenta-derived adherent cell, in the rat neuritis model. Pain is induced in the model by applying carrageenan to the sciatic nerve trunk, causing perineural inflammation of the sciatic nerve. PDA-001, at doses ranging from 0.4×10(6) to 4×10(6) cells/animal, or vehicle control was intravenously administrated to assess the biological activity of the cells. A dose-dependent effect of PDA-001 on pain relief was demonstrated. PDA-001 at doses of 1×10(6) and 4×10(6), but not 0.4×10(6), reduced mechanical hyperalgesia within 24h following treatment and through day 8 after induction of neuritis. The mechanism underlying PDA-001-mediated reduction of neuroinflammatory pain was also explored. Ex vivo tissue analyses demonstrated that PDA-001 suppressed homing, maturation and differentiation of dendritic cells, thus inhibiting T-cell priming and activation in draining lymph nodes. PDA-001 also reduced interferon gamma and IL-17 in draining lymph nodes and in the ispilateral sciatic nerve, and increased the levels of IL-10 in draining lymph nodes and plasma, pointing to T-cell modulation as a possible mechanism mediating the observed anti-hyperalgesic effects. Furthermore, in the ipsilateral sciatic nerve, significantly less leukocyte infiltration was observed in PDA-001-treated animals. The results suggest that PDA-001may provide a novel therapeutic approach in the management of inflammatory neuropathic pain and similar conditions.