Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice.

Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ß (IFN-ß) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.

Potassium channel modulation in macrophages sensitizes dorsal root ganglion neurons after nerve injury.

Macrophages and satellite glial cells are found between injured and uninjured neurons in the lumbar dorsal root ganglia (DRG). We explored the mechanism of neuro-immune and neuron-glia crosstalk leading to hyperexcitability of DRG neurons. After spared nerve injury (SNI), CX3CR1+ resident macrophages became activated, proliferated, and increased inward-rectifying potassium channel Kir 2.1 currents. Conditioned medium (CM) by macrophages, obtained from DRG of SNI mice, sensitized small DRG neurons from naïve mice. However, treatment with CM from GFAP+ glial cells did not affect neuronal excitability. When subjected to this macrophage-derived CM, DRG neurons had increased spontaneous activity, current-evoked responses and voltage-gated NaV 1.7 and NaV 1.8 currents. Silencing Kir 2.1 in macrophages after SNI prevented the induction of neuronal hyperexcitability from their CM. Blocking vesicular exocytosis or soluble tumor necrosis factor in CM or interfering with the downstream intracellular p38 pathway in neurons, also prevented neuronal hyperexcitability. Blocking protein trafficking in neurons reduced the effect of CM, suggesting that the hyperexcitable state resulted from changes in NaV channel trafficking. These results suggest that DRG macrophages, primed by peripheral nerve injury, contribute to neuron-glia crosstalk, NaV channel dysregulation and neuronal hyperexcitability implicated in the development of neuropathic pain.

Characterisation of GFAP-Expressing Glial Cells in the Dorsal Root Ganglion after Spared Nerve Injury.

Satellite glial cells (SGCs), enveloping primary sensory neurons' somas in the dorsal root ganglion (DRG), contribute to neuropathic pain upon nerve injury. Glial fibrillary acidic protein (GFAP) serves as an SGC activation marker, though its DRG satellite cell specificity is debated. We employed the hGFAP-CFP transgenic mouse line, designed for astrocyte studies, to explore its expression within the peripheral nervous system (PNS) after spared nerve injury (SNI). We used diverse immunostaining techniques, Western blot analysis, and electrophysiology to evaluate GFAP+ cell changes. Post-SNI, GFAP+ cell numbers increased without proliferation, and were found near injured ATF3+ neurons. GFAP+ FABP7+ SGCs increased, yet 75.5% of DRG GFAP+ cells lacked FABP7 expression. This suggests a significant subset of GFAP+ cells are non-myelinating Schwann cells (nmSC), indicated by their presence in the dorsal root but not in the ventral root which lacks unmyelinated fibres. Additionally, patch clamp recordings from GFAP+ FABP7-cells lacked SGC-specific Kir4.1 currents, instead displaying outward Kv currents expressing Kv1.1 and Kv1.6 channels specific to nmSCs. In conclusion, this study demonstrates increased GFAP expression in two DRG glial cell subpopulations post-SNI: GFAP+ FABP7+ SGCs and GFAP+ FABP7- nmSCs, shedding light on GFAP's specificity as an SGC marker after SNI.

Friendship in Later Life: How Friends Are Significant Resources in Older Persons' Communication about Chronic Pain.

BACKGROUND: This article focuses on how older persons perceive their friends' role in their daily experience of chronic pain. It reports part of the results of a study in which we interviewed 49 participants, aged 75 and older, about the way they communicate about chronic pain within their social network. METHODOLOGY: Using discourse and content analysis, we first examine older persons' definition of friendship, and then identify the various dimensions of friendship that are engaged in the communication about chronic pain. RESULTS: Participants define close friends as people with whom they share intimacy and social proximity (same gender, age and experience of pain). These dimensions allow older persons to talk freely about their pain without the fear of being judged or rejected, particularly when it is related to a dynamic of reciprocity. CONCLUSIONS: This article shows that the contribution of friends to the everyday life of older persons with chronic pain is mainly that of providing emotional support.

Reversing anterior insular cortex neuronal hypoexcitability attenuates compulsive behavior in adolescent rats.

Development of self-regulatory competencies during adolescence is partially dependent on normative brain maturation. Here, we report that adolescent rats as compared to adults exhibit impulsive and compulsive-like behavioral traits, the latter being associated with lower expression of mRNA levels of the immediate early gene zif268 in the anterior insula cortex (AIC). This suggests that underdeveloped AIC function in adolescent rats could contribute to an immature pattern of interoceptive cue integration in decision making and a compulsive phenotype. In support of this, we report that layer 5 pyramidal neurons in the adolescent rat AIC are hypoexcitable and receive fewer glutamatergic synaptic inputs compared to adults. Chemogenetic activation of the AIC attenuated compulsive traits in adolescent rats supporting the idea that in early stages of AIC maturity there exists a suboptimal integration of sensory and cognitive information that contributes to inflexible behaviors in specific conditions of reward availability.

Talking about chronic pain in family settings: a glimpse of older persons' everyday realities.

BACKGROUND: The expression of chronic pain remains a delicate matter for those older persons who suffer from this condition. If many studies highlight the difficulties of putting pain into words, scarce are those that take into account how given social networks can facilitate or prevent its expression. Based on a qualitative study that explores the communication about chronic pain in older persons' social network, this article reports on this key issue of talking about health in later life within family settings and provides clinicians with information about the way older persons with chronic conditions perceive their everyday realities and social relations. METHODS: A multidisciplinary research team (medicine, linguistics and psychology) interviewed 49 persons with chronic pain, all from the French-speaking part of Switzerland, aged 75 and older, without any major cognitive or auditory impairments. After transcription, the interviews were analyzed by combining content and discourse analysis with social network theories. RESULTS: Communication about chronic pain depends significantly on the position of the interlocutors within the family structure, with a preference for direct relatives or individuals with similar difficulties. In social networks, the ability to communicate about chronic pain is both a resource (by allowing older persons to get help or by strengthening interpersonal relations) and a challenge (by threatening their autonomy, social relations or self-esteem). CONCLUSIONS: The study shows the predominance of the nuclear family (partner, children) in communication relating specifically to the everyday management of chronic pain. This state of affairs is, nevertheless, balanced by issues of (loss of) autonomy. These findings, in line with current trends in geriatrics, could benefit future reflections on the scope and limits of including relatives in the care of older patients with chronic conditions.

The Antidiabetic Drug Metformin Regulates Voltage-Gated Sodium Channel NaV1.7 via the Ubiquitin-Ligase NEDD4-2.

The antidiabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5'-monophosphate protein kinase that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus post-translational expression of voltage-gated sodium channels (NaVs). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of NaV1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when cotransfected with NEDD4-2. Similarly, in voltage-clamp recordings, metformin significantly reduced NaV1.7 current density when cotransfected with NEDD4-2. In mouse dorsal root ganglion (DRG) neurons, without changing the biophysical properties of NaV1.7, metformin significantly decreased NaV1.7 current densities, but not in Nedd4L knock-out mice (SNS-Nedd4L-/-). In addition, metformin induced a significant reduction in NEDD4-2 phosphorylation at the serine-328 residue in DRG neurons, an inhibitory phosphorylation site of NEDD4-2. In current-clamp recordings, metformin reduced the number of action potentials elicited by DRG neurons from Nedd4Lfl/fl , with a partial decrease also present in SNS-Nedd4L-/- mice, suggesting that metformin can also change neuronal excitability in an NEDD4-2-independent manner. We suggest that NEDD4-2 is a critical player for the effect of metformin on the excitability of nociceptive neurons; this action may contribute to the relief of neuropathic pain.

Communication About Chronic Pain in Older Persons' Social Networks: Study Protocol of a Qualitative Approach.

A lack of social relations appears to impact on health and life expectancy among the older persons. The quality and diversity of social relations are correlated with good health and well-being in later life. Chronic pain is a crucial issue in aging population. Effective communication between the older persons with chronic pain, their relatives and the actors of the healthcare system facilitates the management of this condition. Studies on communication in later life generally do not consider the older persons' social network as a whole, focusing only a specific segment (e.g., family or medical staff). This lack of scientific data prevents the actors of the healthcare system from offering solutions to bridge clinically relevant communication gaps. As a consequence, our study has three objectives: (1) to identify how the older persons perceive communication about chronic pain with their social network; (2) to identify their unmet communication needs; (3) to develop recommendations that improve communication about chronic pain in later life. The study will be divided into two phases. The first phase will meet objectives 1 and 2. It will involve individual interviews with about 50 people over 75 years old suffering from chronic pain and without major cognitive or auditory troubles. In this phase, we will apply a multi-layered analysis. We will map the older persons' personal network and identify their communication practices and needs, by combining content and discourse analysis with social network theories. The second phase of the study will aim at recommendations based on the results of the first phase (objective 3). It will require focus groups with different sets of stakeholders (older persons, relative caregivers, health professionals, decision-makers). In the second phase, we will use content analysis to pinpoint the concerns and suggestions for action. The results will be disseminated on three levels: (1) to the scientific world (specialists in the field of health and aging and health communication); (2) to health practitioners working with older persons; (3) to society at large, with a focus on institutions and groups directly concerned by the issue.

Cortico-autonomic local arousals and heightened somatosensory arousability during NREMS of mice in neuropathic pain.

Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid eye movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared nerve injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability.

Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents.

Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.

A test of positive suggestions about side effects as a way of enhancing the analgesic response to NSAIDs.

Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been absorbed, might favor analgesia in a clinical interaction model. Sixty-six healthy males participated in a study "to validate pupillometry as an objective measure of analgesia". Participants were unknowingly randomized double-blind to positive vs control information about side effects embedded in a video regarding the study drugs. Sequences of moderately painful heat stimuli applied before and after treatment with diclofenac and atropine served to evaluate analgesia. Atropine was deceptively presented as a co-analgesic, but used to induce side effects. Adverse events (AE) were collected with the General Assessment of Side Effects (GASE) questionnaire prior to the second induced pain sequence. Debriefing fully informed participants regarding the purpose of the study and showed them the two videos.The combination of medication led to significant analgesia, without a between-group difference. Positive information about side effects increased the attribution of AE to the treatment compared to the control information. The total GASE score was correlated with analgesia, i.e., the more AEs reported, the stronger the analgesia. Interestingly, there was a significant between-groups difference on this correlation: the GASE score and analgesia correlated only in the positive information group. This provides evidence for a selective link between AEs and pain relief in the group who received the suggestion that AEs could be taken as a sign "that help was on the way". During debriefing, 65% of participants said they would prefer to receive the positive message in a clinical context. Although the present results cannot be translated immediately to clinical pain conditions, they do indicate the importance of testing this type of modulation in a clinical context.

Primary care physicians' attitude and reported prescribing behavior for chronic low back pain: An exploratory cross-sectional study.

OBJECTIVE: Recent guidelines for chronic or recurrent low back pain recommend non-pharmacologic treatments as first-line options. The objective of this study was thus to explore the perceived usefulness of several conventional and complementary medicine treatments for chronic or recurrent low back pain by primary care physicians and their reported prescribing behavior. DESIGN: An exploratory cross-sectional study. SETTING AND PARTICIPANTS: Primary care physicians of the French-speaking part of Switzerland. MAIN OUTCOME MEASURES: Primary care physicians' perceived usefulness of each conventional and complementary medicine treatment and their reported recommendation behavior were considered dependent variables in multivariate logistic regression models. All correlations were computed between binary variables, and phi coefficients were calculated to estimate correlation strengths. RESULTS: 533 primary care physicians answered the questionnaire (response rate: 25.6%). The top 3 conventional treatments most often considered useful by primary care physicians for chronic or recurrent low back pain were physiotherapy (94.8%), nonsteroidal anti-inflammatory drugs (87.9%), and manual therapy (82.5%), whereas the most prescribed conventional treatments were physiotherapy (99.2%), nonsteroidal anti-inflammatory drugs (97.4%), and acetaminophen (94.4%). Osteopathic treatment (78.4%), yoga (69.3%), and therapeutic massage (63.9%) were the complementary medicine treatments most often considered useful by primary care physicians in managing chronic or recurrent low back pain. Being a female physician, younger than 56 years, trained in complementary medicine, or using complementary medicine were all associated with higher perceived usefulness of complementary medicine treatments in general. The most recommended complementary medicine treatments by primary care physicians were osteopathic treatment (87.3%), acupuncture (69.3%), and therapeutic massage (58.7%). Being a female physician, younger than 56, and using complementary medicine were all associated with more complementary medicine recommendation in general. CONCLUSION: Our results highlight the importance of better understanding the prescribing patterns of primary care physicians for chronic or recurrent low back pain. Considering the frequency and burden of chronic or recurrent low back pain, programs focusing on the most (cost-) effective treatments should be implemented.

Healthcare professionals' sources of knowledge of complementary medicine in an academic center.

BACKGROUND: Complementary medicine (CM) is utilized in a growing number of academic centers despite the debate concerning its value, risks and benefits. Healthcare professionals often feel uncomfortable discussing CM with patients, and little is known about their sources of knowledge in the field of CM. OBJECTIVE: To assess healthcare professionals' sources of knowledge and attitude toward CM in an academic hospital. DESIGN AND PARTICIPANTS: The cross-sectional web-based survey took place from October to December 2013. A total of 4,925 healthcare professionals working at Lausanne University Hospital, Switzerland, were invited to answer the questionnaire. MAIN MEASURES: Factors influencing healthcare professionals' opinion toward CM, knowledge and communication about CM. KEY RESULTS: The questionnaire was answered by 1,247 healthcare professionals. The three key factors influencing professionals' opinion toward CM were personal experience, clinical experience and evidence demonstrating the physiological mechanism of CM. Personal experience was more associated with nurses' and midwives' opinion compared to physicians' (80.8% vs 57.1%, OR = 3.08, [95% CI: 2.35-4.05], P<0.001 and 85.3% vs 57.1%, OR = 3.83, [95% CI: 1.95-7.53], P<0.001, respectively) as well as with professionals trained in CM compared to non-trained professionals (86.0% vs 73.2%, OR = 2.60, [95% CI: 1.92-3.53], P<0.001). Physicians relied more on randomized controlled clinical trials compared to nurses (81.3% vs 62.9%, OR = 0.43, [95% CI: 0.33-0.57], P<0.001). A majority of the respondents (82.5%) agreed that they lacked knowledge about CM and 65.0% noted that it was the patient who initially started the discussion about CM. CONCLUSIONS: Different professionals used different strategies to forge opinions regarding CM: physicians relied more on scientific evidence, while nurses and midwives were more influenced by personal experience. Regardless of preferred information source, most respondents did not feel prepared to address patient questions regarding CM. Enhancing interprofessional education opportunities is an important strategy to help providers become empowered to discuss CM with patients. This in turn will help patients making informed decisions in their healthcare.

Gene Expression Profiling of Cutaneous Injured and Non-Injured Nociceptors in SNI Animal Model of Neuropathic Pain.

Nociceptors are a particular subtype of dorsal root ganglion (DRG) neurons that detect noxious stimuli and elicit pain. Although recent efforts have been made to reveal the molecular profile of nociceptors in normal conditions, little is known about how this profile changes in pathological conditions. In this study we exploited laser capture microdissection to specifically collect individual injured and non-injured nociceptive DRG neurons and to define their gene profiling in rat spared nerve injury (SNI) model of neuropathic pain. We found minimal transcriptional changes in non-injured neurons at 7 days after SNI. In contrast, several novel transcripts were altered in injured nociceptors, and the global signature of these LCM-captured neurons differed markedly from that the gene expression patterns found previously using whole DRG tissue following SNI. Pathway analysis of the transcriptomic profile of the injured nociceptors revealed oxidative stress as a key biological process. We validated the increase of caspase-6 (CASP6) in small-sized DRG neurons and its functional role in SNI- and paclitaxel-induced neuropathic pain. Our results demonstrate that the identification of gene regulation in a specific population of DRG neurons (e.g., nociceptors) is an effective strategy to reveal new mechanisms and therapeutic targets for neuropathic pain from different origins.

Peripheral nerve injury induces a transitory microglial reaction in the rat infralimbic cortex.

Undeniable evidence shows that microglia in the spinal cord undergo marked reactions following peripheral injuries. However, only rare studies have investigated the possible short and long term microglial reaction in brain regions following peripheral nerve injury and its interspecies specificities. In the present study we examined microglia in subdivisions of the prefrontal cortex in mice and rats, 7days and 42days after spared nerve injury (SNI) of the sciatic nerve. We show that a bilateral increase of microglial density takes place in the infralimbic cortex in rats 7days post-injury (sham vs. SNI, n=5: ipsilateral 35.4% increase of the median, p=0.0317; contralateral 24.9% increase of the median, p=0.0079), without any detectable change in the other investigated regions, namely the anterior cingulate, prelimbic and agranular insular cortices. In mice, no observable difference could be found in any region at both time points, neither using Iba-1 immunostaining nor with CX3CR1-eGFP animals. Our results indicate that a transitory, species-specific and highly regionalized microglial reaction takes place in the prefrontal cortex following peripheral nerve injury.

Chronic low back pain patients' use of, level of knowledge of and perceived benefits of complementary medicine: a cross-sectional study at an academic pain center.

BACKGROUND: Chronic pain patients often use complementary medicine (CM) to alleviate their pain; however, little is known about the use of CM by chronic low back pain (cLBP) patients. We investigated the frequency of use of CM by cLBP patients, the perceived effects of these therapies, patients' knowledge regarding CM, and patient-physician communication regarding CM. METHOD: A cross-sectional survey was conducted from November 2014 to February 2015. A questionnaire was distributed by physicians to 238 consecutive patients consulting for cLBP at the Pain Center of Lausanne University Hospital, Switzerland. Poisson regression model was used to analyze patients' level of knowledge regarding various CMs, and the logistic regression model was used to assess CM use for cLBP. RESULTS: The questionnaire was returned by 168 cLBP patients (response rate: 70.6%). Lifetime prevalence of CM use for cLBP was 77.3%. The most commonly used therapies were osteopathy (48.8%), massage (45.2%) and acupuncture (31.6%), rated for their usefulness on a 0-10 scale as a mean ± SD of 5.4 ± 2.7, 5.9 ± 2.5 and 3.8 ± 3.2, respectively. The CM treatment best known by patients was osteopathy, followed by massage and acupuncture. If their doctors proposed CM as a treatment for cLBP, 78% of participants reported being very or somewhat likely to try CM. Respondents with CM health insurance were more likely to use CM (OR = 2.26; 95%CI: 1.07-4.78; p = 0.031) for cLBP. Respondents having experienced cLBP for more than five years were more likely to use CM to treat their cLBP than respondents having experienced cLBP for one year or less (OR = 2.84; 95%CI: 1.02-7.88; p = 0.044). CONCLUSIONS: More than three-quarters of cLBP patients in our sample did use CM to treat their cLBP. The results showed that the most commonly used therapies were not necessarily the highest rated in terms of perceived usefulness. These results highlight the importance of developing integrative pain centers in which patients may obtain advice regarding CM treatments.

The Attitudes of Physicians, Nurses, Physical Therapists, and Midwives Toward Complementary Medicine for Chronic Pain: A Survey at an Academic Hospital.

OBJECTIVE: To assess the attitudes of physicians, nurses, physical therapists, and midwives toward complementary medicine (CM) at a Swiss academic hospital and toward its use for treating chronic pain. DESIGN: The cross-sectional survey took place from October to December 2013. SETTING: An e-mail sent to 4925 healthcare professionals (1969 physicians, 2372 nurses, 145 physical therapists, and 111 midwives) working at Lausanne University Hospital, Switzerland, invited them to answer a web-based questionnaire. RESULTS: The questionnaire was answered by 1247 healthcare professionals (response rate: 25.3%). Of these, 96.1% strongly agreed or agreed that CM could be useful for the treatment of chronic pain, with more nurses (96.7%) and midwives (100%) than physicians (93.8%) agreeing that CM could be useful (P < .001 for both comparisons). Women had more positive attitude toward CM than men (97.8% versus 91.2%; P < .001). Of the respondents, 96.9% were strongly in favor or in favor of offering CM, especially hypnosis (89.8%), osteopathy (85.5%), and acupuncture (83.4%), at the hospital for treating chronic pain. Respondents listed migraine (74.7%), tension headaches (70.6%), and low back pain (70.1%) as three main conditions for which they would refer patients for acupuncture. The three therapies with which respondents were the most unfamiliar were neuraltherapy (57.2%), mindfulness-based stress reduction (MBSR) (54.1%), and biofeedback (51.9%). Over half of respondents, 58.3%, had never referred a patient to a CM practitioner. A total of 84.3% of the respondents felt that they lacked the knowledge to inform their patients about CM.

Spinal Cord T-Cell Infiltration in the Rat Spared Nerve Injury Model: A Time Course Study.

The immune system is involved in the development of neuropathic pain. In particular, the infiltration of T-lymphocytes into the spinal cord following peripheral nerve injury has been described as a contributor to sensory hypersensitivity. We used the spared nerve injury (SNI) model of neuropathic pain in Sprague Dawley adult male rats to assess proliferation, and/or protein/gene expression levels for microglia (Iba1), T-lymphocytes (CD2) and cytotoxic T-lymphocytes (CD8). In the dorsal horn ipsilateral to SNI, Iba1 and BrdU stainings revealed microglial reactivity and proliferation, respectively, with different durations. Iba1 expression peaked at D4 and D7 at the mRNA and protein level, respectively, and was long-lasting. Proliferation occurred almost exclusively in Iba1 positive cells and peaked at D2. Gene expression observation by RT-qPCR array suggested that T-lymphocytes attracting chemokines were upregulated after SNI in rat spinal cord but only a few CD2/CD8 positive cells were found. A pronounced infiltration of CD2/CD8 positive T-cells was seen in the spinal cord injury (SCI) model used as a positive control for lymphocyte infiltration. Under these experimental conditions, we show early and long-lasting microglia reactivity in the spinal cord after SNI, but no lymphocyte infiltration was found.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

Neuropathic Pain Phenotype Does Not Involve the NLRP3 Inflammasome and Its End Product Interleukin-1ß in the Mice Spared Nerve Injury Model.

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is one of the main sources of interleukin-1ß (IL-1ß) and is involved in several inflammatory-related pathologies. To date, its relationship with pain has not been studied in depth. The aim of our study was to elucidate the role of NLRP3 inflammasome and IL-1ß production on neuropathic pain. Results showed that basal pain sensitivity is unaltered in NLRP3-/- mice as well as responses to formalin test. Spared nerve injury (SNI) surgery induced the development of mechanical allodynia and thermal hyperalgesia in a similar way in both genotypes and did not modify mRNA levels of the NLRP3 inflammasome components in the spinal cord. Intrathecal lipopolysaccharide (LPS) injection increases apoptosis-associated speck like protein (ASC), caspase-1 and IL-1ß expression in both wildtype and NLRP3-/- mice. Those data suggest that NLRP3 is not involved in neuropathic pain and also that other sources of IL-1ß are implicated in neuroinflammatory responses induced by LPS.