Changes In Nociception Research Articles

The Effect of Preoperative Intra-Articular Methylprednisolone on Pain After TKA: A Randomized Double-Blinded Placebo Controlled Trial in Patients With High-Pain Knee Osteoarthritis and Sensitization

Peripherally driven inflammatory pain and nociceptive changes before TKA has been suggested to be a cause for increased acute postoperative pain. However, preoperative intra-articular MP in patients with high pain osteoarthritis and sensitization did not reduce acute post-TKA pain or sensitization despite a preoperative reduction of intra-articular inflammatory markers.

The role of C-fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

To evaluate C fiber-mediated changes in bladder sensation and nociception in an animal model of stress induced bladder hyperalgesia and urinary frequency. Female Wistar-Kyoto (WKY) rats were exposed to a chronic (10 days) water avoidance stress (WAS) and compared to controls. Rats were evaluated by cystometrogram (CMG) and visceromotor reflex (VMR) to bladder infusion with room temperature (RT) or cold saline. Cold saline activates afferent C-fibers via cold bladder receptors. To further evaluate bladder hyperalgesia, CMG and VMR were also obtained during RT isometric bladder distention (RT-iBD) at variable pressures. During RT infusion, WAS rats had significant decreases in pressure threshold (PT) and in the ratio of VMR threshold/maximum intravesical pressure (IVPmax), and a significant increase in VMR duration. Cold infusion also induced significant decreases in PT and in the ratio of VMR threshold/IVPmax in WAS rats. During RT-iBD, rats exposed to WAS showed a significant decrease in VMR latency and a significant increase in VMR area under the curve (AUC) compared to controls. Chronic WAS induced bladder hypersensitivity manifested by earlier voiding with earlier VMR appearance. Chronic stress also enhanced bladder nociceptive responses. WAS leads to increase responses to ice cold water infusion, implying a role of sensitized C-fibers and mechanoreceptors in WAS-induced bladder dysfunction and hypersensitivity.

Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway.

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans.SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs.

The water avoidance stress induces bladder pain due to a prolonged alpha1A adrenoceptor stimulation.

Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) remains an elusive disease with the cause for the pain unclear. BPS/IC patients present increased sympathetic activity and high levels of urinary noradrenaline. At the experimental level, it has been shown that chronic adrenergic stimulation produces pain and bladder changes through an alpha 1A adrenoceptor mediated mechanism. Water avoidance stress (WAS) in rodents reproduces signs of nociception and bladder changes seen in BPS/IC patients. In this study, we explore the possible role of alpha 1A adrenoceptor in bladder pain and morphological changes. WAS was induced in a group of female Wistar rats. A separate WAS group received 0.2mg/kgday silodosin (WAS+S). Lower abdominal pain was determined by performing sensitivity to Von Frey filaments. Bladder reflex activity was determined by cystometry in anaesthetised animals. Urine was collected for noradrenaline quantification by HPLC. Bladders were harvested and stained with Haematoxylin-eosin (to analyse urothelial morphology and to determine the disruption of surface umbrella cells) or with Toluidine Blue 0.1% to analyse mast cell infiltration. WAS increased urinary noradrenaline level and bladder frequency and decreased mechanical pain threshold, which was reversed by silodosin. WAS induced lymphocytic and mast cells infiltration in the mucosa and mild urothelial disruption, which was absent in WAS+S group. Alpha 1A adrenoceptor stimulation has an important role in the appearance of bladder pain in rats. Since BPS/IC patients present high levels of noradrenaline, alpha 1A stimulation may be an additional trigger for bladder dysfunction presented by these patients. Further studies will determine the clinical relevance of this finding in the treatment of BPS/IC patients.

Chronic stress-induced mechanical hyperalgesia is controlled by capsaicin-sensitive neurones in the mouse.

Clinical studies demonstrated peripheral nociceptor deficit in stress-related chronic pain states, such as fibromyalgia. The interactions of stress and nociceptive systems have special relevance in chronic pain, but the underlying mechanisms including the role of specific nociceptor populations remain unknown. We investigated the role of capsaicin-sensitive neurones in chronic stress-related nociceptive changes. Capsaicin-sensitive neurones were desensitized by the capsaicin analogue resiniferatoxin (RTX) in CD1 mice. The effects of desensitization on chronic restraint stress (CRS)-induced responses were analysed using behavioural tests, chronic neuronal activity assessment in the central nervous system with FosB immunohistochemistry and peripheral cytokine concentration measurements. Chronic restraint stress induced mechanical and cold hypersensitivity and increased light preference in the light-dark box test. Open-field and tail suspension test activities were not altered. Adrenal weight increased, whereas thymus and body weights decreased in response to CRS. FosB immunopositivity increased in the insular cortex, dorsomedial hypothalamic and dorsal raphe nuclei, but not in the spinal cord dorsal horn after the CRS. CRS did not affect the cytokine concentrations of hindpaw tissues. Surprisingly, RTX pretreatment augmented stress-induced mechanical hyperalgesia, abolished light preference and selectively decreased the CRS-induced neuronal activation in the insular cortex. RTX pretreatment alone increased the basal noxious heat threshold without influencing the CRS-evoked cold hyperalgesia and augmented neuronal activation in the somatosensory cortex and interleukin-1α and RANTES production. Chronic restraint stress induces hyperalgesia without major anxiety, depression-like behaviour or peripheral inflammatory changes. Increased stress-induced mechanical hypersensitivity in RTX-pretreated mice is presumably mediated by central mechanisms including cortical plastic changes. These are the first data demonstrating the complex interactions between capsaicin-sensitive neurones and chronic stress and their impact on nociception. Capsaicin-sensitive neurones are protective against stress-induced mechanical hyperalgesia by influencing neuronal plasticity in the brain.

Physiological and Pharmacokinetic Effects of E‐cigarette Type Exposure to Δ9‐Tetrahydrocannabinol (THC)

The increase in availability of electronic cigarettes (e‐cigarettes) for delivery of nicotine has led to the adaptation of these devices for the delivery of marijuana. Although there have been studies investigating the effects of intrapulmonary delivery of Δ9‐tetrahydrocannabinol (THC), no studies have investigated the effects of e‐cigarette type exposure in rodents. The goal of this study was to determine if vapor delivery of THC using e‐cigarette technology would produce cannabinoid‐typical effects observed in rodents using other routes of administration. Male Wistar rats received an injection of THC (0.3–10 mg/kg,i.p.) or were exposed to vaporized THC or crude marijuana extract in propylene glycol (PG) vehicle (200 mg/mL and 400 mg/mL respectively; 4 puffs per 5 min for 10–40 min). Rats were tested for changes in body temperature and nociception, and plasma THC content was analyzed using fast liquid chromatography/mass spectrometry (LC/MS). Vapor exposure to THC or crude extract significantly reduced body temperature up to 165 min following vape initiation. Tail flick latency was assessed using a hot water bath (52°C), and results showed increased latency up to 60 min post‐vape initiation. Plasma THC levels following a 10 mg/kg intraperitoneal injection were similar to levels produced by 30 min of inhalation exposure to THC in PG. Our results demonstrate that intrapulmonary delivery of THC using‐e‐cigarette type devices produces physiological effects, and this study validates this novel method of intrapulmonary THC delivery in rats.Support or Funding InformationDA024105 and DA035482

Home cage wheel running is an objective and clinically relevant method to assess inflammatory pain in male and female rats

BackgroundThe assessment of nociception in preclinical studies is undergoing a transformation from pain-evoked to pain-depressed tests to more closely mimic the effects of clinical pain. Many inflammatory pain-depressed behaviors (reward seeking, locomotion) have been examined, but these tests are limited because of confounds such as stress and difficulties in quantifying behavior. New methodThe present study evaluates home cage wheel running as an objective method to assess the magnitude and duration of inflammatory pain in male and female rats. ResultsInjection of Complete Freund's Adjuvant (CFA) into the right hindpaw to induce inflammatory pain almost completely inhibited wheel running for 2 days in male and female rats. Wheel running gradually returned to baseline levels within 12 days despite persistent mechanical hypersensitivity (von Frey test). Comparison with existing methodsContinuously monitoring home cage wheel running improves on previous studies examining inflammatory pain-depressed wheel running because it is more sensitive to noxious stimuli, avoids the stress of removing the rat from its cage for testing, and provides a complete analysis of the time course for changes in nociception. ConclusionsThe present data indicate that home cage wheel running is a clinically relevant method to assess inflammatory pain in the rat. The decrease in activity caused by inflammatory pain and subsequent gradual recovery mimics the changes in activity caused by pain in humans. The tendency for pain-depressed wheel running to be greater in female than male rats is consistent with the tendency for women to be at greater risk of chronic pain than men.

Acute versus chronic phase mechanisms in a rat model of CRPS.

BackgroundTibia fracture followed by cast immobilization in rats evokes nociceptive, vascular, epidermal, and bone changes resembling complex regional pain syndrome (CRPS). In most cases, CRPS has three stages. Over time, this acute picture, allodynia, warmth, and edema observed at 4 weeks, gives way to a cold, dystrophic but still painful limb. In the acute phase (at 4 weeks post fracture), cutaneous immunological and NK1-receptor signaling mechanisms underlying CRPS have been discovered; however, the mechanisms responsible for the chronic phase are still unknown. The purpose of this study is to understand the mechanisms responsible for the chronic phases of CRPS (at 16 weeks post fracture) at both the peripheral and central levels.MethodsWe used rat tibial fracture/cast immobilization model of CRPS to study molecular, vascular, and nociceptive changes at 4 and 16 weeks post fracture. Immunoassays and Western blotting were carried out to monitor changes in inflammatory response and NK1-receptor signaling in the skin and spinal cord. Skin temperature and thickness were measured to elucidate vascular changes, whereas von Frey testing and unweighting were carried out to study nociceptive changes. All data were analyzed by one-way analysis of variance (ANOVA) followed by Neuman-Keuls multiple comparison test to compare among all cohorts.ResultsIn the acute phase (at 4 weeks post fracture), hindpaw allodynia, unweighting, warmth, edema, and/or epidermal thickening were observed among 90 % fracture rats, though by 16 weeks (chronic phase), only the nociceptive changes persisted. The expression of the neuropeptide signaling molecule substance P (SP), NK1 receptor, inflammatory mediators TNFα, IL-1β, and IL-6 and nerve growth factor (NGF) were elevated at 4 weeks in sciatic nerve and/or skin, returning to normal levels by 16 weeks post fracture. The systemic administration of a peripherally restricted IL-1 receptor antagonist (anakinra) or of anti-NGF inhibited nociceptive behaviors at 4 weeks but not 16 weeks. However, spinal levels of NK1 receptor, TNFα, IL-1β, and NGF were elevated at 4 and 16 weeks, and intrathecal injection of an NK1-receptor antagonist (LY303870), anakinra, or anti-NGF each reduced nociceptive behaviors at both 4 and 16 weeks.ConclusionsThese results demonstrate that tibia fracture and immobilization cause peripheral changes in neuropeptide signaling and inflammatory mediator production acutely, but central spinal changes may be more important for the persistent nociceptive changes in this CRPS model.

Experimental allergic encephalomyelitis: peculiarities of pain-relieving therapy and place of anti¬con¬vulsants as analgetics.

Multiple sclerosis (MS) is the most common demyelinating disease affecting mainly young people of the working age (16-45 years) and quickly leading to disability. Available data constitute that up to 80% of MS patients suffer from pain at different disease periods. Pain management and the analgesic drug choice in MS patients may be difficult. Anticonvulsant drugs possess an analgesic activity and are widely used in patients presenting painful neuropathic symptoms. Based on that, we aimed to investigate the nociceptive potential changes as well as the research-oriented behavior using the open field test in rat. An experimental animal equivalent of multiple sclerosis has been modeled, based on the methylprednisolone (M) administration. Animals were also administered anticonvulsants (carbamazepine, topiramate, sodium volproat, pregabalin and gabapentin). The stu­dy showed advantages of gabapentin and pregabalin use in simulated disease treatment. This statement is based on the open field test results, where the motor-oriented rats’ behavior was evaluated. Administration of M+gabapentin and M+pregabalin showed positive dynamics of the motor activity: the number of squares crossed increased by 80.86% (p<0.05) and 81.73% (р<0.05) respectively. Maximum recovery of the research activity (peeking in mink) was re­gis­tered in animals administered M+pregabalin: the increase rate was 300% (r<0.05) comparing with the 12 th day of ex­periment. It was shown, that 5-days administration of M+gabapentin and M+pregabalin caused muscle tone impro­ve­ment by 190% (p<0.05) and 200% (p<0.05) respectively, comparing with animals with untreated multiple sclerosis. A sig­ni­fi­cant increase of analgesic activity of M+pregabalin and M+gabapentin combinations used together with me­thyl­pred­nisolone by 4.1 (p<0.05) and 3.6 (p<0.05) times was registered comparing with the initial methylprednisolone background.

Nociceptive Reactions in Rats during Repeated Stress Exposure.

Changes in nociceptive sensitivity of rats with various behavioral patterns in the open-field test were studied after repeated stress exposure on the model of daily 4-h immobilization for 8 days. The tail-flick latency in response to light-heat stimulation in passive and active specimens decreased most significantly on days 2 and 7, respectively. However, this parameter did not differ from the baseline on day 8 of observations. Vocalization threshold during electrocutaneous stimulation in behaviorally active animals did not change over the first 7 days of repeated stress exposure, but increased significantly on day 8 of the study. The emotional component of nociception in passive animals increased on day 3, but decreased on days 4 and 6 of the experiment. Therefore, repeated stress exposure in rats is mainly accompanied by an increase in the perceptual component of nociception. Variations in the emotional component of nociceptive sensitivity after stress loads are manifested in the initial increase and subsequent decrease in this parameter. The observed changes are more pronounced in behaviorally passive rats than in active animals. These data illustrate the specifics of stress-induced changes in nociception of specimens with various individual and typological characteristics. Our results hold much promise for the development of new individual approaches to modulation of pain sensitivity in humans under conditions of negative emotiogenic exposures.

Neuroimmune and Neuropathic Responses of Spinal Cord and Dorsal Root Ganglia in Middle Age.

Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that CD2, CD3e, CD68, CD45, TNF-α, IL6, CCL2, ATF3 and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in CCL2, and IL6, and elevated ATF3 mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased ATF3); whereas, levels of GFAP protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain.

Referred pain and cutaneous responses from deep tissue electrical pain stimulation in the groin

Persistent postherniotomy pain is located around the scar and external inguinal ring and is often described as deep rather than cutaneous, with frequent complaints of pain in adjacent areas. Whether this pain is due to local pathology or referred/projected pain is unknown, hindering mechanism-based treatment. Deep tissue electrical pain stimulation by needle electrodes in the right groin (rectus muscle, ilioinguinal/iliohypogastric nerve and perispermatic cord) was combined with assessment of referred/projected pain and the cutaneous heat pain threshold (HPT) at three prespecified areas (both groins and the lower right arm) in 19 healthy subjects. The assessment was repeated 10 days later to assess the reproducibility of individual responses. Deep electrical stimulation elicited pain at the stimulation site in all subjects, and in 15 subjects, pain from areas outside the stimulation area was reported, with 90-100% having the same response on both days, depending on the location. Deep pain stimulation significantly increased the cutaneous HPT (P<0.014). Individual HPT responses before and during deep electrical pain stimulation were significantly correlated (ρ>0.474, P≤0.040) at the two test days for the majority of test areas. Our results corroborate a systematic relationship between deep pain and changes in cutaneous nociception. The individual referred/projected pain patterns and cutaneous responses are variable, but reproducible, supporting individual differences in anatomy and sensory processing. Future studies investigating the responses to deep tissue electrical stimulation in persistent postherniotomy pain patients may advance our understanding of underlying pathophysiological mechanisms and strategies for treatment and prevention. ClinicalTrials.gov (NCT01701427).

Identification of Spinal Cord MicroRNA and Gene Signatures in a Model of Chronic Stress-Induced Visceral Hyperalgesia in Rat.

IntroductionAnimal studies have shown that stress could induce epigenetic and transcriptomic alterations essential in determining the balance between adaptive or maladaptive responses to stress. We tested the hypothesis that chronic stress in rats deregulates coding and non-coding gene expression in the spinal cord, which may underline neuroinflammation and nociceptive changes previously observed in this model.MethodsMale Wistar rats were exposed to daily stress or handled, for 10 days. At day 11, lumbar spinal segments were collected and processed for mRNA/miRNA isolation followed by expression profiling using Agilent SurePrint Rat Exon and Rat miRNA Microarray platforms. Differentially expressed gene lists were generated using the dChip program. Microarrays were analyzed using the Ingenuity Pathways Analysis (IPA) tool from Ingenuity Systems. Multiple methods were used for the analysis of miRNA-mRNA functional modules. Quantitative real time RT-PCR for Interleukin 6 signal transducer (gp130), the Signal Transducer And Activator Of Transcription 3 (STAT3), glial fibrillary acidic protein and mir-17-5p were performed to confirm levels of expression.ResultsGene network analysis revealed that stress deregulated different inflammatory (IL-6, JAK/STAT, TNF) and metabolic (PI3K/AKT) signaling pathways. MicroRNA array analysis revealed a signature of 39 deregulated microRNAs in stressed rats. MicroRNA-gene network analysis showed that microRNAs are regulators of two gene networks relevant to inflammatory processes. Specifically, our analysis of miRNA-mRNA functional modules identified miR-17-5p as an important regulator in our model. We verified miR-17-5p increased expression in stress using qPCR and in situ hybridization. In addition, we observed changes in the expression of gp130 and STAT3 (involved in intracellular signaling cascades in response to gp130 activation), both predicted targets for miR-17-5p. A modulatory role of spinal mir17-5p in the modulation of visceral sensitivity was confirmed in vivo.ConclusionUsing an integrative high throughput approach, our findings suggest a link between miR-17-5p increased expression and gp130/STAT3 activation providing new insight into the possible mechanisms mediating the effect of chronic stress on neuroinflammation in the spinal cord.

Effects of Single and Long-Term Treatment with Caffeine on the Chronic Unpredictable Stress-Induced Changes in Nociception in Rodents

Effects of Single and Long-Term Treatment with Caffeine on the Chronic Unpredictable Stress-Induced Changes in Nociception in Rodents

Involvement of Melatonin in Changes in Nociception in Mollusks and Mice in Long-Term Electromagnetic Screening

Electromagnetic screening for several days induced triphasic changes in nociception in mollusks and mice: an initial phase of hyperalgesia was followed by an antinociceptive phase and subsequent normalization of measures of nociception. In mollusks, these changes developed more slowly and the hyperalgesia phase was more marked than in mice. Daily administration of melatonin to the animals eliminated the screening-induced hyperalgesia and induced an earlier and more marked antinociceptive effect. These changes appeared to be linked with initial suppression of melatonin secretion by electromagnetic screening, resulting in hyperalgesia. Melatonin secretion then increased, which was apparent as an increase in the antinociceptive effect.

Sex differences in a Murine Model of Complex Regional Pain Syndrome

Complex Regional Pain Syndrome (CRPS) is a major cause of chronic pain after surgery or trauma to the limbs. Despite evidence showing that the prevalence and severity of many forms of chronic pain, including CRPS, differ between males and females, laboratory studies on sex-related differences in animal models of CRPS are not available, and the impact of sex on the transition from acute to chronic CRPS pain and disability are unexplored. Here we make use of a tibia fracture/cast mouse model that recapitulates the nociceptive, functional, vascular, trophic, inflammatory and immune aspects of CRPS. Our aim is to describe the chronic time course of nociceptive, motor and memory changes associated with fracture/cast in male and female mice, in addition to exploring their underlying spinal mechanisms. Our behavioral data shows that, compared to males, female mice display lower nociceptive thresholds following fracture in the absence of any differences in ongoing or spontaneous pain. Furthermore, female mice show exaggerated signs of motor dysfunction, deficits in fear memory, and latent sensitization that manifests long after the normalization of nociceptive thresholds. Our biochemical data show differences in the spinal cord levels of the glutamate receptor NR2b, suggesting sex differences in mechanisms of central sensitization that could account for differences in duration and severity of CRPS symptoms between the two groups.

Contribution and interaction of kinin receptors and dynorphin A in a model of trigeminal neuropathic pain in mice

Infraorbital nerve constriction (CION) causes hypersensitivity to facial mechanical, heat and cold stimulation in rats and mice and is a reliable model to study trigeminal neuropathic pain. In this model there is evidence that mechanisms operated by kinin B1 and B2 receptors contribute to heat hyperalgesia in both rats and mice. Herein we further explored this issue and assessed the role of kinin receptors in mechanical hyperalgesia after CION. Swiss and C57Bl/6 mice that underwent CION or sham surgery or dynorphin A (1–17) administration were repeatedly submitted to application of either heat stimuli to the snout or mechanical stimuli to the forehead. Treatment of the animals on the fifth day after CION surgery with DALBK (B1 receptor antagonist) or HOE-140 (B2 receptor antagonist), both at 0.01–1μmol/kg (i.p.), effectively reduced CION-induced mechanical hyperalgesia. Knockout mice for kinin B1, B2 or B1/B2 receptors did not develop heat or mechanical hyperalgesia in response to CION. Subarachnoid dynorphin A (1–17) delivery (15nmol/5μL) also resulted in orofacial heat hyperalgesia, which was attenuated by post-treatment with DALBK (1 and 3μmol/kg, i.p.), but was not affected by HOE-140. Additionally, treatment with an anti-dynorphin A antiserum (200μg/5μL, s.a.) reduced CION-induced heat hyperalgesia for up to 2h. These results suggest that both kinin B1 and B2 receptors are relevant in orofacial sensory nociceptive changes induced by CION. Furthermore, they also indicate that dynorphin A could stimulate kinin receptors and this effect seems to contribute to the maintenance of trigeminal neuropathic pain.

Defensive Behavior against Noxious Heat Stimuli Is Declined with Aging Due to Decreased Pain-Associated Gene Expression in Drosophila

Aging is defined as a collective process that alters organism’s functional capacity and appearance over the course of life. Apart from an increase in susceptibility to many diseases, aging affects the cellular system that is responsible for decoding painful stimuli. Yet, aging-associated molecular mechanisms of pain perception remains elusive. Using Drosophila, we showed a decrease in temperature tolerance and a reduction in high temperature thermal avoidance with aging. Locomotor activity assay demonstrated that the age-dependent changes in heat nociception did not stem from the general decline in muscular activity. However, we identified pain-related gene expression alteration with aging. We anticipate that our findings would help opening a new window onto developing the optimal pain treatment for the elderly.

Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization.

Tibia fracture induces exaggerated substance P (SP) and calcitonin gene-related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postfracture hind limb nociceptive sensitization. At 4 weeks after performing tibia fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in fracture rats. Transgenic fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postfracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postfracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent fracture model of complex regional pain syndrome.

A role for Kalirin-7 in nociceptive sensitization via activity-dependent modulation of spinal synapses.

Synaptic plasticity is the cornerstone of processes underlying persistent nociceptive activity-induced changes in normal nociceptive sensitivity. Kalirin-7 is a multifunctional guanine-nucleotide-exchange factor (GEF) for Rho GTPases that is characterized by its localization at excitatory synapses, interactions with glutamate receptors and its ability to dynamically modulate the neuronal cytoskeleton. Here we show that spinally expressed Kalirin-7 is required for persistent nociceptive activity-dependent synaptic long-term potentiation as well as activity-dependent remodelling of synaptic spines in the spinal dorsal horn, thereby orchestrating functional and structural plasticity during the course of inflammatory pain.