Regulation Of Pain Sensitivity Research Articles

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity

Spinal RAMP1-mediated neuropathic pain sensitisation in the aged mice through the modulation of CGRP-CRLR pain signalling

Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

Systems genetics analysis reveals the common genetic basis for pain sensitivity and cognitive function.

There is growing evidence of a strong correlation between pain sensitivity and cognitive function under both physiological and pathological conditions. However, the detailed mechanisms remain largely unknown. In the current study, we sought to explore candidate genes and common molecular mechanisms underlying pain sensitivity and cognitive function with a transcriptome-wide association study using recombinant inbred mice from the BXD family. The pain sensitivity determined by Hargreaves' paw withdrawal test and cognition-related phenotypes were systematically analyzed in 60 strains of BXD mice and correlated with hippocampus transcriptomes, followed by quantitative trait locus (QTL) mapping and systems genetics analysis. The pain sensitivity showed significant variability across the BXD strains and co-varies with cognitive traits. Pain sensitivity correlated hippocampual genes showed a significant involvement in cognition-related pathways, including glutamatergic synapse, and PI3K-Akt signaling pathway. Moreover, QTL mapping identified a genomic region on chromosome 4, potentially regulating the variation of pain sensitivity. Integrative analysis of expression QTL mapping, correlation analysis, and Bayesian network modeling identified Ring finger protein 20 (Rnf20) as the best candidate. Further pathway analysis indicated that Rnf20 may regulate the expression of pain sensitivity and cognitive function through the PI3K-Akt signaling pathway, particularly through interactions with genes Ppp2r2b, Ppp2r5c, Col9a3, Met, Rps6, Tnc, and Kras. Our study demonstrated that pain sensitivity is associated with genetic background and Rnf20-mediated PI3K-Akt signaling may involve in the regulation of pain sensitivity and cognitive functions.

Progesterone Receptor Activation Regulates Sensory Sensitivity and Migraine Susceptibility

Women develop chronic pain during their reproductive years more often than men, and estrogen and progesterone regulate this susceptibility. We tested whether brain progesterone receptor (PR) signaling regulates pain susceptibility. During the estrous cycle, animals were more sensitive to mechanical stimulus during the estrus stage than in the diestrus stage, suggesting a role for reproductive hormones, estrogen, and progesterone. Progesterone treatment of ovariectomized and estrogen-primed mice caused a delayed reduction in the mechanical threshold. Segesterone, a specific agonist of PRs replicated this effect, whereas, the segesterone-induced reduction in mechanical threshold was blocked in the mice lacking PRs in the nervous system. Segesterone treatment also did not alter mechanical threshold in adult male and juvenile female mice. PR activation increased the cold sensitivity but did not affect the heat and light sensitivity. We evaluated whether PR activation altered experimental migraine. Segesterone and nitroglycerin when administered sequentially, reduced the pain threshold but not when given separately. PRs were expressed in several components of the migraine ascending pain pathway, and their deletion blocked the painful effects of nitroglycerin. PR activation also increased the number of active neurons in the components of the migraine ascending pain pathway. These studies have uncovered a pain-regulating function of PRs. Targeting PRs may provide a novel therapeutic avenue to treat chronic pain and migraine in women. PerspectiveThis article provides evidence for the role of progesterone receptors in regulating pain sensitivity and migraine susceptibility in females. Progesterone receptors may be a therapeutic target to treat chronic pain conditions more prevalent in women than men.

The microbiota-gut-brain axis regulates motivation for exercise.

The microbiota-gut-brain axis regulates motivation for exercise.

JMJD8 regulates neuropathic pain by affecting spinal cord astrocyte differentiation

The demethylase JmjC structural domain-containing protein 8 (JMJD8) has been demonstrated to be involved in cellular inflammatory responses. Neuropathic pain (NP) is a chronic pain, and it is unclear whether JMJD8 is involved in the regulation of NP. Using a chronic constriction injury (CCI) mouse model of NP, we investigated the expression levels of JMJD8 during NP and the influences of JMJD8 on regulating pain sensitivity. We found that JMJD8 expression in the spinal dorsal horn was reduced after CCI. Immunohistochemistry showed that JMJD8 was colabeled with GFAP in naïve mice. Knockdown of JMJD8 in the spinal dorsal horn astrocytes induced pain behavior. Further study showed that overexpression of JMJD8 in the spinal dorsal horn astrocytes not only reversed pain behavior but also activated the spinal dorsal horn A1 astrocytes. These results suggest that JMJD8 may modulate pain sensitivity by affecting activated the spinal dorsal horn A1 astrocytes and may be a potential therapeutic target for NP.

The role of dorsal root ganglia alpha-7 nicotinic acetylcholine receptor in complete Freund's adjuvant-induced chronic inflammatory pain.

Alpha-7 nicotinic acetylcholine receptor (α7nAChR) was reported to have a critical role in the regulation of pain sensitivity and neuroinflammation. However, the expression level of α7nAChR in dorsal root ganglion (DRG) and the underlying neuroinflammatory mechanisms associated with hyperalgesia are still unknown. In the present study, the expression and mechanism of α7nAChR in chronic inflammatory pain was investigated using a complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model. Subsequently, a series of assays including immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. α7nAChR was mostly colocalized with NeuN in DRG and upregulated after CFA injection. Microinjection of α7nAChR siRNA into ipsilateral L4/5 DRGs aggravated the CFA-induced pain hypersensitivity. Intrathecal α7nAChR agonist GTS-21 attenuated the development of CFA-induced mechanical and temperature-related pain hypersensitivities. In neuronal the SH-SY5Y cell line, the knockdown of α7nAChRs triggered the upregulation of TRAF6 and NF-κB under CFA-induced inflammatory conditions, while agitation of α7nAChR suppressed the TRAF6/NF-κB activation. α7nAChR siRNA also exacerbated the secretion of pro-inflammatory mediators from LPS-induced SH-SY5Y cells. Conversely, α7nAChR-specific agonist GTS-21 diminished the release of interleukin-1beta (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNFα) in SH-SY5Y cells under inflammatory conditions. Mechanistically, the modulation of pain sensitivity and neuroinflammatory action of α7nAChR may be mediated by the TRAF6/NF-κB signaling pathway. The findings of this study suggest that α7nAChR may be potentially utilized as a therapeutic target for therapeutics of chronic inflammatory pain.

Effect of Social Support in Pain Sensitivity in Children with Cerebral Palsy and Typically Developing Children.

Pain and abnormal somatosensory processing are important associated conditions in children and adolescents with cerebral palsy (CP). Perceived social support is highly relevant for pain perception and coping. Aim: The aim of the present study was to assess the influence of social support on pain sensitivity in children and adolescents with cerebral palsy and healthy peers. Design: Cross-sectional study. Methods: Pressure pain thresholds were assessed in 42 children and adolescents with CP and 190 healthy peers during three different conditions: alone, with their mother and with a stranger. Results: Children with CP reported lower pain sensitivity when they were with their mother than being alone or with a stranger, whereas healthy peers did not experience different pain sensitivity related to the social condition. Sex or clinical characteristics did not affect the relationship between pain perception and social support. Conclusion: The present study shows how children with CP are highly affected by social and contextual influences for regulating pain sensitivity. Solicitous parental support may enhance pain perception in children with CP. Further research on the topic is warranted in order to attain well-founded conclusions for clinical practice.

Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex.

Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become "unsilenced" by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.

The α7 nicotinic acetylcholine receptor positive allosteric modulator prevents lipopolysaccharide-induced allodynia, hyperalgesia and TNF-α in the hippocampus in mice.

Previous studies have shown that α7 nicotinic acetylcholine receptor (nAChR) has a critical role in the regulation of pain sensitivity and neuroinflammation. However, pharmacological effects of α7 nAChR activation in the hippocampus on neuroinflammatory mechanisms associated with allodynia and hyperalgesia remain unknown. We have determined the effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an α7 nAChR positive allosteric modulator, on lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in mice. We also evaluated the effects of TQS on immunoreactivity of microglial marker ionized-calcium binding adaptor molecule 1 (Iba-1), phospho-nuclear factor-κB (p-NF-κB p65), tumor necrosis factor-alpha (TNF-α), and norepinephrine (NE) level. Mice were treated with (0.25, 1 or 4 mg/kg, ip) followed by LPS (1 mg/kg, ip) administration. Allodynia and hyperalgesia were determined using von Frey filaments and hot plate respectively. Immunoreactivity of Iba-1, p-NF-κB p65, and TNF-α, were measured in the hippocampus using immunofluorescence assay. Hippocampal NE level was evaluated using high performance liquid chromatography. LPS administration resulted in allodynia and hyperalgesia in mice after six h. Systemic administration of TQS prevented LPS-induced allodynia and hyperalgesia. TQS pretreatment significantly decreased the immunoreactivity of Iba-1, p-NF-κB, and TNF-α in CA1 and DG regions of the hippocampus. In addition, TQS reversed LPS-induced NE reduction in the hippocampus. Taken together, our results suggest that TQS prevented LPS-induced allodynia and hyperalgesia, upregulation of TNF-α expression and NE level reduction involving microglial α7 nAChR in part in the hippocampus. Therefore, these findings highlight the important effects of α7 nAChR allosteric modulator against symptoms of inflammatory pain.

Kindlin-1 Regulates Astrocyte Activation and Pain Sensitivity in Rats With Neuropathic Pain.

Astrocyte activation has been implicated in the pathogenesis of neuropathic pain, but the involvement of kindlin-1 in astrocyte activation and neuropathic pain has not yet been illustrated. Using a chronic constriction injury (CCI) rat model of neuropathic pain, we investigated the expression levels of kindlin-1 during neuropathic pain and the influences of kindlin-1 on regulating pain sensitivity. Neuropathic pain was induced in rats by CCI of the sciatic nerve. Rats were randomly assigned to 4 groups: sham operation, CCI, CCI + kindlin-1 short hairpin RNA (shRNA), and CCI + kindlin-1 groups. Animals in the CCI + kindling-1 shRNA and CCI + kindlin-1 groups were given kindlin-1 shRNA or kindlin-1 virus infection to reduce or overexpress kindlin-1, respectively. Kindlin-1 expression was persistently increased in rats 10 days after CCI. A large proportion of glial fibrillary acidic protein (GFAP)-positive astrocytes expressed kindlin-1 in spinal cord tissues of rats after CCI. Compared with the sham operation group, CCI animals exhibited increased GFAP expression and GFAP-positive astrocytes in the spinal cord. Down-regulation of kindlin-1 reduced the up-regulation of GFAP in the spinal cord, whereas overexpression of kindlin-1 promoted elevation of GFAP levels. Kindlin-1 silencing elevated the mechanical and thermal pain thresholds of CCI rats (P < 0.05). However, overexpression of kindlin-1 aggravated CCI-induced pain sensitivity. Kindlin-1 may regulate pain sensitivity by affecting activated astrocytes in the spinal cord. Inhibition of kindlin-1 may provide a novel paradigm for the management of neuropathic pain.

Induction of α6 and β1 integrins by acupuncture stimulation in rats

Acupuncture therapy is performed by applying the needle insertion at discrete cutaneous locations and used for the treatments of diverse symptoms and disorders. In order to elucidate mechanistic basis on how acupuncture stimulation (AS) produces therapeutic effects, it is primarily important to understand tissue responses locally at the acupuncture site (acupoint). Here, we investigated integrin protein as molecular target responding to and integrating AS. Signals of α6 and β1 integrins were clearly induced at zusanli acupoint 24 h after AS in areas of nuclear clusters around the needle track. Induction levels of integrin were largely reduced by needle insertion at non-acupuncture point or without needle rotation. Phospho-Erk1/2 was initially decreased below the basal level after AS but increased 24 h later. Induction pattern of phospho-Erk1/2 was as similar as that of α6 integrin in its selectivity to needling procedure and tissue distribution. We further found that mRNA expression of P2X3 purinergic receptor was upregulated in the dorsal root ganglion (DRG) after AS, but decreased by the inhibition of Erk1/2 activity at the acupuncture area. Moreover, AS-mediated integrin activation was required for Erk1/2 activation at the acupuncture site and regulation of pain sensitivity in the hind paw. The present results provide a new evidence on acupuncture-specific tissue response in terms of integrin induction, and further suggest that integrin activation may be involved in transmitting mechanosensory signals from the acupoint to afferent nerve fiber.

Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome.

Complex regional pain syndrome type 1 (CRPS-I) is a disabling and frequently chronic condition. It involves the extremities and is a frequent consequence of distal tibia and radius fractures. The inflamed appearance of the affected CRPS-I limb suggests that local production of inflammatory mediators may be implicated in the ensuing etiology. A rodent tibia fracture model, characterized by inflammation, chronic unilateral hindlimb warmth, edema, protein extravasation, allodynia and hyperalgesia resembles the clinical features of patients with acute CRPS-I. N-palmitoylethanolamine (PEA), a member of the family of naturally-occurring N-acylethanolamines, is well-known for its ability to modulate inflammatory processes and regulate pain sensitivity. However, the large particle size and lipidic nature of PEA may limit its bioavailability and solubility when given orally. Micronized formulations are frequently used to enhance the dissolution rate of drug and reduce its variability of absorption when orally administered. The aim of this study was to assess the effects of a formulation of micronized and ultramicronized PEA (PEA-MPS), given orally in a mouse model of CRPS-I. CD-1 male mice were subjected to distal tibia fracture and divided into two groups: control and treated with PEA-MPS (PEA micronized 300 mg/kg and ultramicronized 600 mg/kg). Sensibility to pain was monitored in all mice throughout the course of the experiment. Twenty-eight days after tibia fracture induction animals were sacrificed and biochemical parameters evaluated. The PEA-MPS-treated group showed an improved healing process, fracture recovery and fibrosis score. PEA-MPS administration decreased mast cell density, nerve growth factor, matrix metalloproteinase 9 and cytokine expression. This treatment also reduced (poly-ADP)ribose polymerase activation, peroxynitrite formation and apoptosis. Our results suggest that PEA-MPS may be a new therapeutic strategy in the treatment of CRPS-I.

Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions.

It is well known that interferons (IFNs), such as type-I IFN (IFN-α) and type-II IFN (IFN-γ) are produced by immune cells to elicit antiviral effects. IFNs are also produced by glial cells in the CNS to regulate brain functions. As a proinflammatory cytokine, IFN-γ drives neuropathic pain by inducing microglial activation in the spinal cord. However, little is known about the role of IFN-α in regulating pain sensitivity and synaptic transmission. Strikingly, we found that IFN-α/β receptor (type-I IFN receptor) was expressed by primary afferent terminals in the superficial dorsal horn that co-expressed the neuropeptide CGRP. In the spinal cord IFN-α was primarily expressed by astrocytes. Perfusion of spinal cord slices with IFN-α suppressed excitatory synaptic transmission by reducing the frequency of spontaneous excitatory postsynaptic current (sEPSCs). IFN-α also inhibited nociceptive transmission by reducing capsaicin-induced internalization of NK-1 and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial dorsal horn neurons. Finally, spinal (intrathecal) administration of IFN-α reduced inflammatory pain and increased pain threshold in naïve rats, whereas removal of endogenous IFN-α by a neutralizing antibody induced hyperalgesia. Our findings suggest a new form of neuronal-glial interaction by which IFN-α, produced by astrocytes, inhibits nociceptive transmission in the spinal cord.

Effects of Corticotropin-Releasing Factor (CRF) on Somatic Pain Sensitivity in Conscious Rats: Involvement of Types 1 and 2 CRF Receptors

Corticotropin-releasing factor (CRF) is involved in the regulation of pain sensitivity and can cause an analgesic effect in animals and humans. The aim of the study was to investigate the involvement of CRF1 and CRF2 receptors in CRF-induced analgesic effect (after intraperitoneal injection) on somatic pain sensitivity in conscious rats. Somatic pain sensitivity was tested by tail flick latency (tail flick test). The involvement of CRF1 and CRF2 receptors was studied by their selective antagonists NBI 27914 and astressin 2B, respectively. Systemic administration of CRF caused an increase in tail flick latency (analgesic effect). Pretreatment with NBI 27914 or astressin 2B eliminated CRF-induced analgesic effect. Besides, NBI 27914, but not astressin 2B, increased basal tail flick latency. The data obtained indicate that the analgesic effect can be mediated by both CRF1 and CRF2 receptors. CRF-1 receptor, in contrast to the CRF2 receptors, may be involved in the regulation of the basal level of pain sensitivity.

Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1

cAMP signaling plays a key role in regulating pain sensitivity. Here, we uncover a previously unidentified molecular mechanism in which direct phosphorylation of the exchange protein directly activated by cAMP 1 (EPAC1) by G protein kinase 2 (GRK2) suppresses Epac1-to-Rap1 signaling, thereby inhibiting persistent inflammatory pain. Epac1(-/-) mice are protected against inflammatory hyperalgesia in the complete Freund's adjuvant (CFA) model. Moreover, the Epac-specific inhibitor ESI-09 inhibits established CFA-induced mechanical hyperalgesia without affecting normal mechanical sensitivity. At the mechanistic level, CFA increased activity of the Epac target Rap1 in dorsal root ganglia of WT, but not of Epac1(-/-), mice. Using sensory neuron-specific overexpression of GRK2 or its kinase-dead mutant in vivo, we demonstrate that GRK2 inhibits CFA-induced hyperalgesia in a kinase activity-dependent manner. In vitro, GRK2 inhibits Epac1-to-Rap1 signaling by phosphorylation of Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain. This phosphorylation event inhibits agonist-induced translocation of Epac1 to the plasma membrane, thereby reducing Rap1 activation. Finally, we show that GRK2 inhibits Epac1-mediated sensitization of the mechanosensor Piezo2 and that Piezo2 contributes to inflammatory mechanical hyperalgesia. Collectively, these findings identify a key role of Epac1 in chronic inflammatory pain and a molecular mechanism for controlling Epac1 activity and chronic pain through phosphorylation of Epac1 at Ser-108. Importantly, using the Epac inhibitor ESI-09, we validate Epac1 as a potential therapeutic target for chronic pain.

Sex divide seen in mechanism that produces persistent pain

Research showing that male and female mice regulate pain sensitivity differently raises questions about gender balance in experimental design.

Pain Genetics and Personalized Spine Care

Spine pain (SP), such as low back pain, is among the most common musculoskeletal disorders and is the single most common disorder causing disability in industrialized countries.1 This pain is typically recurrent; 24 to 87% of individuals who have an episode of SP will suffer a recurrence within 1 year.2 The precise causes of SP and its recurrence are poorly understood due to the heterogenic nature of SP and variety of etiological factors including spine injury, herniated disc, spinal stenosis, osteoarthritis (spondylolysis), fractures (osteomyelitis), deformities, scoliosis, ankylosing spondylitis, bacterial infection, and tumor.3 Physical findings and structural spine abnormalities do not always reflect patient-reported symptoms.4 The relationship between spine degeneration and SP is complex and needs more investigation. Psychosocial risk factors have consistently emerged as predictors of the course of SP.5 Unfortunately, results of treatment interventions targeting these risk factors have yielded mixed picture suggesting that there may be other important factors that have not been examined. Genetic approach may reveal hidden mechanisms underlying interindividual variability in SP phenotypes within the same etiology.6 Recently, several genetic factors have been identified contributing to SP phenotypes and may serve as potential pharmaceutical targets. For example, common polymorphism in SCN9A, a gene encoding Nav1.7 channel, was associated with higher pain postdiscectomy.7 Similarly, common allele in KCNS1 gene encoding for potassium channel subunit, were associated with pain severity in two different SP cohorts.8 Therefore, manipulating these genes/alleles or modifying factors that interact with their effects on pain may lead to pain relief in patients with risk genotypes. Other genes may “protect” from SP, such as GCH1, a gene encoding GTP cyclohydrolase, a key enzyme for catecholamine, serotonin, and nitric oxide production.9 Patients carrying two copies of “protective” allele may have better outcomes from spinal surgery in terms of chronic pain and functioning, so for them it becomes the treatment of choice. Genetic approaches applied to SP research may help identify important molecular factors that may contribute to the risk for or protection against chronicity and recurrence. It is highly likely that the interactions among genes, psychosocial and psychophysical factors will shape SP experience.10 Findings from human genetic association studies in painful conditions including SP and DDD have important clinical relevance and will eventually lead to personalized spine care. These will include “genetic signatures” of the risk for severe pain or pain chronification as well as patient's response to pain medicine. Disclosure of Interest None declared References Volinn E. The epidemiology of low back pain in the rest of the world. A review of surveys in low- and middle-income countries. Spine 1997;22(15):1747–1754 Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J 2008;8(1):8–20 Kent PM, Keating JL. The epidemiology of low back pain in primary care. Chiropr Osteopat 2005;13:13 Hoy D, Brooks P, Blyth F, Buchbinder R. The Epidemiology of low back pain. Best Pract Res Clin Rheumatol 2010;24(6):769–781 Feyer AM, Herbison P, Williamson AM, et al. The role of physical and psychological factors in occupational low back pain: a prospective cohort study. Occup Environ Med 2000;57(2):116–120 Young EE, Lariviere WR, Belfer I. Genetic basis of pain variability: recent advances. J Med Genet 2012;49(1):1–9 Reimann F, Cox JJ, Belfer I, et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci U S A 2010;107(11):5148–5153 Costigan M, Belfer I, Griffin RS, et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 2010;133(9):2519–2527 Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med 2006;12(11):1269–1277 Belfer I. Nature and nurture of human pain. Scientifica 2013;2013:415279

Role of colchicine-induced microtubule depolymerization in hyperalgesia via TRPV4 in rats with chronic compression of the dorsal root ganglion

The aim of this study is to investigate the effect of microtubule depolymerization by colchicine on hyperalgesia mediated by transient receptor potential vanilloid 4 (TRPV4) in a neuropathic pain model of chronic compression of the dorsal root ganglion (DRG) (hereafter termed CCD) in rat. Intrathecal administration of microtubule-depolymerizing agent, colchicine, attenuated the activated effect of 4alpha-phorbol 12, 13-didecanoate (4alpha-PDD, TRPV4 specific agonist) on mechanical and thermal hyperalgesia in CCD rats. This observation is in agreement with our in vitro experiments with DRG cells that showed a significant attenuation of 4alpha-PDD-activated Ca2+-influx and substance P (SP) release with the colchicine treatment. We conclude that microtubule depolymerization by colchicine can regulate pain sensitivity by depressing the hyperalgesia mediated by TRPV4.

Protein kinase C gamma (PKCγ) as a novel marker to assess the functional status of the corticospinal tract in experimental autoimmune encephalomyelitis (EAE)

In the spinal cord, PKCγ is an important kinase found in a specific subset of excitatory interneurons in the superficial dorsal horn and in axons of the corticospinal tract (CST). The major interest in spinal PKCγ has been its influences on regulating pain sensitivity but its presence in the CST also indicates that it has a significant role in locomotor function. A hallmark feature of the animal model commonly used to study Multiple Sclerosis, experimental autoimmune encephalolomyelitis (EAE) are motor impairments associated with the disease. More recently, it has also become recognized that EAE is associated with significant changes in pain sensitivity. Given its role in generating pain hypersensitivity and its presence in a major tract controlling motor activity, we set out to characterize whether EAE was associated with changes PKCγ levels in the spinal cord. We show here that EAE triggers a significant reduction in the levels of PKCγ, primarily in the CST. We did not observe any significant changes in PKCγ levels in the superficial dorsal horn but in general the levels tended to be below control levels in this region. In a final experiment we assessed the levels of PKCγ in the spinal cord of EAE mice that had recovered gross locomotor function and compared this to the levels found in EAE mice with chronic deficits. Our findings demonstrate that PKCγ levels are dynamic and that in later stages of the disease, its expression is dependent on the degree of motor function in the model. Taken together these results suggest that PKCγ may be a useful marker in the disease to monitor the status of the CST.