Spontaneous Pain Behavior Research Articles

The function of P2X3 receptor and NK1 receptor antagonists on cyclophosphamide-induced cystitis in rats

The purpose of the study is to explore the function of P2X3 and NK1 receptors antagonists on cyclophosphamide (CYP)-induced cystitis in rats. Sixty female Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the control group were intraperitoneally (i.p.) injected with 0.9% saline (4 ml/kg); the rats in the model group were i.p. injected with CYP (150 mg/kg); and the rats in the intervention group were i.p. injected with CYP with subsequently perfusion of bladder with P2X3 and NK1 receptors' antagonists, Suramin and GR 82334. Spontaneous pain behaviors following the administration of CYP were observed. Urodynamic parameters, bladder pressure-volume curve, maximum voiding pressure (MVP), and maximum cystometric capacity (MCC), were recorded. Pathological changes in bladder tissue were observed. Immunofluorescence was used to detect the expression of P2X3 and NK1 receptors in bladder. Cyclophosphamide treatment increased the spontaneous pain behaviors scores. The incidence of bladder instability during urine storage period of model group was significantly higher than intervention group (χ(2) = 7.619, P = 0.007) and control group (χ(2) = 13.755, P = 0.000). MCC in the model group was lower than the control and intervention groups (P < 0.01). Histological changes evident in model and intervention groups rats' bladder included edema, vasodilation, and infiltration of inflammatory cells. In model group, the expression of P2X3 receptor increased in urothelium and suburothelium, and NK1 receptor increased in suburothelium, while the expression of them in intervention group was lower. In CYP-induced cystitis, the expression of P2X3 and NK1 receptors increased in urothelium and/or suburothelium. Perfusion of bladder with P2X3 and NK1 receptors antagonists ameliorated the bladder function.

Interleukin-33 mediates formalin-induced inflammatory pain in mice

Interleukin-33 (IL-33), a member of the IL-1 family, has attracted growing interest since its discovery in 2003. IL-33 has been implicated in many diseases, including arthritis, asthma, allergies, and cardiovascular and infectious diseases. However, few studies have investigated its role in the transmission and modulation of pain. The present study was designed to explore the possible roles of IL-33 and its receptor, ST2, in formalin-induced inflammatory pain in mice. We found that both subcutaneous (s.c., 300ng) and intrathecal injection (i.t., 3ng) of recombinant IL-33 (rIL-33) increased paw lifting and licking time not only in normal mice but also in formalin models. Administration of ST2 antibody, which blocked the IL-33/ST2 signaling, alleviated the formalin-induced spontaneous pain behavior. Moreover, the ST2−/− mice showed significantly decreased pain behavior, as well as reduced ultrasonic vocalization induced by formalin, compared with the wild-type group. Additionally, ST2 antibody alleviated the potentiating effects of rIL-33 on pain behavior in the formalin mice, indicating that IL-33 plays a role in pain modulation through its ST2 receptor. These data suggest IL-33 and its ST2 receptor mediate formalin-induced inflammatory pain, and as a result this cytokine and its receptor may be new targets for the development of analgesics.

Animal models of bone cancer pain: Systematic review and meta-analyses

Pain can significantly decrease the quality of life of patients with advanced cancer. Current treatment strategies often provide inadequate analgesia and unacceptable side effects. Animal models of bone cancer pain are used in the development of novel pharmacological approaches. Here we conducted a systematic review and meta-analysis of publications describing in vivo modelling of bone cancer pain in which behavioural, general health, macroscopic, histological, biochemical, or electrophysiological outcomes were reported and compared to appropriate controls. In all, 150 publications met our inclusion criteria, describing 38 different models of bone cancer pain. Reported methodological quality was low; only 31% of publications reported blinded assessment of outcome, and 11% reported random allocation to group. No publication reported a sample size calculation. Studies that reported measures to reduce bias reported smaller differences in behavioural outcomes between tumour-bearing and control animals, and studies that presented a statement regarding a conflict of interest reported larger differences in behavioural outcomes. Larger differences in behavioural outcomes were reported in female animals, when cancer cells were injected into either the tibia or femur, and when MatLyLu prostate or Lewis Lung cancer cells were used. Mechanical-evoked pain behaviours were most commonly reported; however, the largest difference was observed in spontaneous pain behaviours. In the spinal cord astrocyte activation and increased levels of Substance P receptor internalisation, c-Fos, dynorphin, tumor necrosis factor-α and interleukin-1β have been reported in bone cancer pain models, suggesting several potential therapeutic targets. However, the translational impact of animal models on clinical pain research could be enhanced by improving methodological quality.

Activation of p38 mitogen-activated protein kinase in the dorsal root ganglion contributes to pain hypersensitivity after plantar incision

BackgroundThe phosphorylation of p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglion (DRG) promotes primary afferent sensitization. The role of p38MAPK signaling in the DRG in the pathogenesis of plantar incision hyperalgesia has not been investigated. ResultsLevels of phosphorylated p38MAPK (p-p38MAPK) obviously increased in the DRG after plantar incision. Unmyelinated and myelinated DRG neurons that express p-p38MAPK contained small to medium cell bodies, suggesting that p-p38MAPK expression is induced in neurons with C- and Aδ-fibers. The p-p38MAPK inhibitors FR167653 or SB203580 inhibited incision-induced mechanical hypersensitivity and spontaneous pain behavior. The systemic administration of tumor necrosis factor-α (TNF-α) inhibitor prevented subsequent incision-induced activation of p38MAPK in the DRG and alleviated mechanical hypersensitivity after the incision. Conclusionsp38MAPK signaling in the DRG plays a crucial role in the development of primary afferent sensitization and pain behavior caused by plantar incision.

Activation of Src Family Kinases in Spinal Microglia Contributes to Formalin-Induced Persistent Pain State Through p38 Pathway

Protein tyrosine phosphorylation has been implicated in normal and pathological functions such as cell proliferation, migration and differentiation. Recently, some studies have shown that Src family kinases (SFKs) were involved in neurological disorders and neuropathic pain states in which microglial activation plays a role. In the formalin test, we have reported that microglia undergo at least 2 distinct stages of activation on the basis of signaling events regarding p38 mitogen-activated protein kinases (MAPK). Here, we investigated the involvement of SFKs signaling in a formalin pain animal model and the association with p38 MAPK. Our results showed that SFKs were activated in the spinal microglia beginning 1 day after peripheral formalin injection lasting for 7 days. Pretreatment with SFK specific inhibitor PP2 could not inhibit formalin-induced spontaneous pain behaviors. However, PP2 inhibited formalin injury, induced persistent mechanical hyperalgesia, and reversed microglial phospho-p38 expression as well using immunohistostaining and Western blot at day 3 and 7 after injection. Our results suggested that the activation of the Src/p38MAPK signaling cascade in spinal microglia contributed to late stage persistent mechanical hyperalgesia evoked by formalin injection into the paw. PerspectiveThis study presents unique properties of spinal microglial activation in a pain animal model. This finding could potentially help clinicians to further understand the contributions of spinal microglia to acute and persistent pain state.

Patterns of nerve injury and neuropathic pain in ischemic neuropathy after ligation‐reperfusion of femoral artery in mice

Ischemia is an important etiology of painful neuropathies. We generated a mouse system of ischemic neuropathy by ligation-reperfusion of the femoral artery to mimic neuropathic pain and nerve injury patterns observed clinically. Mice exhibited spontaneous neuropathic pain behaviors, which were most obvious after ischemia for 5 h. Mechanical and cold allodynia developed by post-operative day (POD) 7 and persisted through the experimental period up to POD 56. Neuropathic pain behaviors were alleviated with intraperitoneal gabapentin (50 and 100 mg/kg) in a dose-dependent manner. Large-fiber deficit assessed with nerve conduction studies was demonstrated by reduced amplitudes of the compound muscle action potential (CMAP) on POD 7 (48.4% of the control side, p < 0.001). Small-fiber impairment was demonstrated by decreased epidermal nerve density (END) on POD 7 (29.1% of the control side, p < 0.001). Reductions in CMAP amplitudes and ENDs persisted through POD 56. Our system replicated the clinical manifestations of ischemic neuropathy: (1) neuropathic pain with cold and mechanical allodynia and (2) nerve injury to both large and small fibers with pathologic and physiologic evidence. This system produced by a simple procedure provides an opportunity to investigate mechanisms and further treatments of ischemic neuropathy on genetically engineered mice.

Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling

Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that intraplantar injection of P-CTX-1 elicits cold allodynia in mice by targeting specific unmyelinated and myelinated primary sensory neurons. These include both tetrodotoxin-resistant, TRPA1-expressing peptidergic C-fibres and tetrodotoxin-sensitive A-fibres. P-CTX-1 does not directly open heterologously expressed TRPA1, but when co-expressed with Na(v) channels, sodium channel activation by P-CTX-1 is sufficient to drive TRPA1-dependent calcium influx that is responsible for the development of cold allodynia, as evidenced by a large reduction of excitatory effect of P-CTX-1 on TRPA1-deficient nociceptive C-fibres and of ciguatoxin-induced cold allodynia in TRPA1-null mutant mice. Functional MRI studies revealed that ciguatoxin-induced cold allodynia enhanced the BOLD (Blood Oxygenation Level Dependent) signal, an effect that was blunted in TRPA1-deficient mice, confirming an important role for TRPA1 in the pathogenesis of cold allodynia.

HYP-1, a novel diamide compound, relieves inflammatory and neuropathic pain in rats

In the present study, we investigated whether a novel compound, 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethylamino)-N-(3,4,5-trimethoxybenzyl)acetamide (HYP-1), is capable of binding to voltage-gated sodium channels (VGSCs) and evaluated both its inhibitory effect on Na+ currents of the rat dorsal root ganglia (DRG) sensory neuron and its in vivo analgesic activity using rat models of inflammatory and neuropathic pain. HYP-1 showed not only high affinity for rat sodium channel (site 2), but also potent inhibitory activity against the TTX-R Na+ currents of the rat DRG sensory neuron. HYP-1 co-injected with formalin (5%, 50μl) under the plantar surface of rat hind paw dose-dependently reduced spontaneous pain behaviors during both the early and late phases. This result was confirmed by c-Fos immunofluorescence in the L4-5 spinal segments. A large number of c-Fos-positive neurons were observed in rat injected with a mixture of formalin and vehicle, but not in rat treated with a mixture of formalin and HYP-1. In addition, the effectiveness of HYP-1 (6 and 60mg/kg, i.p.) in suppression of neuropathic pain, such as mechanical, cold and warm allodynia, induced by rat tail nerve injury was investigated. HYP-1 showed limited selectivity over hERG, N-type and T-type channels. Our present results indicate that HYP-1, as a VGSC blocker, has potential analgesic activities against nociceptive, inflammatory and neuropathic pain.

Transient Receptor Potential Ankyrin 1 as a Target for Perioperative Pain Management

Transient Receptor Potential Ankyrin 1 as a Target for Perioperative Pain Management

Effects of Low Power Laser on Pain Response and Axonal Regeneration in Rat Models with Sciatic Nerve Crush Injury

This study purposed to examine the effect of low power laser on pain response and axonal regeneration. In order to prepare peripheral nerve injury models, we crushed the sciatic nerve of Sprague-Dawley rats and treated them with low power laser for 21 days. The rats were divided into 4 groups: normal group(n=10); control group(n=10) without any treatment after the induction of sciatic nerve crush injury; experimental group I(n=10) treated with low power laser(0.21<TEX>$mJ/mm^2$</TEX>) after the induction of sciatic nerve crush injury; and experimental group II(n=10) treated with low power laser(5.25<TEX>$mJ/mm^2$</TEX>) after the induction of sciatic nerve crush injury. We measured spontaneous pain behavior(paw withdrawal latency test) and mechanical allodynia(von Frey filament test) for evaluating pain behavioral response, and measured the sciatic function index for evaluating the functional recovery of peripheral nerve before the induction of sciatic nerve crush injury and on day 1, 7, 14 and 21 after the induction. After the experiment was completed, changes in the H & E stain and toluidine blue stain were examined histopathologically, and changes in MAG(myelin associated glycoprotein) and c-fos were examined immunohistologically. According to the results of this study, when low power laser was applied to rat models with sciatic nerve crush injury for 21 days and the results were examined through pain behavior evaluation and neurobehavioral, histopathological and immunohistological analyses, low power laser was found to affect pain response and axonal regeneration in both experimental group I and experimental group II. Moreover, the effect on pain response and axonal regeneration was more positive in experimental group I to which output 0.21<TEX>$mJ/mm^2$</TEX> was applied than in experimental group II to which 5.25<TEX>$mJ/mm^2$</TEX> was applied.

Automated measurement of spontaneous pain‐associated limb movement and drug efficacy evaluation in a rat model of neuropathic pain

The withdrawal response elicited by a nociceptive stimulus, i.e., evoked pain measure, is commonly used as an efficacy endpoint in neuropathic pain animal models. It, however, has several limitations, which highlight the importance of examining spontaneous pain. The present study describes an automated method for measuring spontaneous pain behaviour in a rat model of neuropathic pain caused by chronic constriction injury (CCI) of sciatic nerve. After CCI surgery, a small magnet was implanted into the operated limb. The rat was placed in a test chamber that was surrounded by wire coil. Limb movements, including lifting/guarding, flinching/shaking, licking and walking in the operated limb, caused changes in the electromagnetic field, including a change in voltage and transformed into a signal via an amplifier. CCI rats consistently showed more frequent limb movement than sham rats. There was no significant correlation between the frequency of spontaneous pain behaviour and the evoked pain symptoms. Treatment with duloxetine (30 mg/kg p.o.) and amitriptyline (30 and 100 mg/kg p.o.) significantly reduced this frequency. Pregabalin at 30 mg/kg p.o. tended to reduce the frequency, and diclofenac up to 10 mg/kg p.o. had no effect. A non-subjective automated method for measuring spontaneous pain behaviour in an animal model of neuropathic pain was established. It is expected that the current system will greatly enhance the analysis of spontaneous pain-related behaviour, which is a predominant symptom in patients with neuropathic pain. The current system may also be valuable in the screening of potential analgesic treatments.

Periaqueductal gray stimulation suppresses spontaneous pain behavior in rats

Methods for evaluating analgesic effect for spontaneous pain are increasingly important because it is reported by most patients with neuropathic pain. The present study assessed the analgesic effects of periaqueductal gray (PAG) stimulation in the spared nerve injury (SNI) model of neuropathic pain of the rat. Spontaneous rapid paw withdrawal movements were used as the index of spontaneous pain. Deep-brain stimulation in the PAG was performed in rats 3 weeks after SNI. Significant analgesic effects on spontaneous pain behavior were observed at the same stimulation parameter that reversed the reduced mechanical threshold of the von Frey test. Both analgesic effects lasted 30–40min beyond the 3min stimulation period. In summary, PAG stimulation was effective in alleviating spontaneous pain and mechanical allodynia in the SNI rat. The frequency of spontaneous paw lifting, a behavioral index of spontaneous pain used in this study, will be useful for future testing of therapeutic methods.

Leak K+ channel mRNAs in dorsal root ganglia: Relation to inflammation and spontaneous pain behaviour

Two pore domain potassium (K2P) channels (KCNKx.x) cause K+leak currents and are major contributors to resting membrane potential. Their roles in dorsal root ganglion (DRG) neurons normally, and in pathological pain models, are poorly understood. Therefore, we examined mRNA levels for 10 K2P channels in L4 and L5 rat DRGs normally, and 1day and 4days after unilateral cutaneous inflammation, induced by intradermal complete Freund's adjuvant (CFA) injections. Spontaneous foot lifting (SFL) duration (spontaneous pain behaviour) was measured in 1day and 4day rats <1h before DRG harvest. mRNA levels for KCNK channels and Kv1.4 relative to GAPDH (n=4–6 rats/group) were determined with real-time RT-PCR. This study is the first to demonstrate expression of THIK1, THIK2 and TWIK2 mRNA in DRGs. Abundance in normal DRGs was, in descending order:Kv1.4>TRESK(KCNK18)>TRAAK(KCNK4)>TREK2(KCNK10)=TWIK2(KCNK6)>TREK1 (KCNK2)=THIK2(KCNK12)>TASK1(KCNK3)>TASK2(KCNK5)>THIK1(KCNK13)=TASK3(KCNK9).During inflammation, the main differences from normal in DRG mRNA levels were bilateral, suggesting systemic regulation, although some channels showed evidence of ipsilateral modulation. By 1day, bilateral K2P mRNA levels had decreased (THIK1) or increased (TASK1, THIK2) but by 4days they were consistently decreased (TASK2, TASK3) or tended to decrease (excluding TRAAK). The decreased TASK2 mRNA was mirrored by decreased protein (TASK2-immunoreactivity) at 4days. Ipsilateral mRNA levels at 4days compared with 1day were lower (TRESK, TASK1, TASK3, TASK2 and THIK2) or higher (THIK1). Ipsilateral SFL duration during inflammation was positively correlated with ipsilateral TASK1 and TASK3 mRNAs, and contralateral TASK1, TRESK and TASK2 mRNAs. Thus changes in K2P mRNA levels occurred during inflammation and for 4 K2P channels were associated with spontaneous pain behaviour (SFL). K2P channels and their altered expression are therefore associated with inflammation-induced pain.

Blocking EphB1 Receptor Forward Signaling in Spinal Cord Relieves Bone Cancer Pain and Rescues Analgesic Effect of Morphine Treatment in Rodents

Treating bone cancer pain continues to be a clinical challenge and underlying mechanisms of bone cancer pain remain elusive. Here, we report that EphB1 receptor forward signaling in the spinal cord is critical to the development of bone cancer pain and morphine tolerance in treating bone cancer pain. Tibia bone cavity tumor cell implantation (TCI) produces bone cancer-related thermal hyperalgesia, mechanical allodynia, spontaneous and movement-evoked pain behaviors, and bone destruction. Production and persistence of these pain behaviors are well correlated with TCI-induced upregulation of EphB1 receptor and its ligand ephrinB2 in the dorsal horn and primary sensory neurons. Spinal administration of an EphB1 receptor blocking reagent EphB2-Fc prevents and reverses bone cancer pain behaviors and the associated induction of c-Fos and activation of astrocytes and microglial cells, NR1 and NR2B receptors, Src within the N-methyl-D-aspartate receptor complex, and the subsequent Ca(2+)-dependent signals. The exogenous ligand ephrinB2-Fc upregulates level of phosphorylation of NR1 and NR2B receptors depending on the activation of EphB1 receptor. Spinal administration of EphB2-Fc and ephrinB2-Fc induces downregulation of EphB1 and ephrinB2, respectively, accompanied with increased activity of matrix metalloproteinase (MMP)-2/9. Blocking MMP-2 or MMP-9 reverses EphB1-Fc treatment-induced downregulation of EphB1 receptor. In addition, spinal blocking or targeted mutation of EphB1 receptor reverses morphine tolerance in treating bone cancer pain in rats and defensive pain in mice. These findings show a critical mechanism underlying the pathogenesis of bone cancer pain and suggest a potential target for treating bone cancer pain and improving analgesic effect of morphine clinically.

Spinal neuroplasticity in chronic pain

Abstract Neuroplastic changes play an important role in the generation and maintenance of chronic pain syndromes. Such changes occur at all levels of the neuraxis, from the peripheral terminals of primary sensory neurons to the cerebral cortex. Changes observed in the spinal dorsal horn in particular provide a mechanistic basis for many of the characteristics of chronic pain syndromes. While facilitated synaptic transmission between nociceptive fibers and spinal projection neurons contributes to enhanced perception of noxious stim­uli (hyperalgesia), diminished function of GA­BA-ergic and glycinergic interneurons not only induces hyperalgesia, but also triggers no­ciceptive reactions on exposure to innocuous stimuli and spontaneous pain behavior in the absence of any sensory stimulation. Spinal disinhibition thus recapitulates typical symptoms of chronic pathological pain syndromes. Studies performed by various groups over the last 10 years demonstrate that such spinal disinhibition occurs naturally in response to peripheral inflammation and nerve dam­age. The present article summarizes current status of this research.

Acid-Sensing Ion Channels in Postoperative Pain

Iatrogenic pain consecutive to a large number of surgical procedures has become a growing health concern. The etiology and pathophysiology of postoperative pain are still poorly understood, but hydrogen ions appear to be important in this process. We have investigated the role of peripheral acid-sensing ion channels (ASICs), which form depolarizing channels activated by extracellular protons, in a rat model of postoperative pain (i.e., hindpaw skin/muscle incision). We report high levels of ASIC-type currents (∼ 77%) in sensory neurons innervating the hindpaw muscles, with a prevalence of ASIC3-like currents. The ASIC3 protein is largely expressed in lumbar DRG neurons innervating the plantar muscle, and its mRNA and protein levels are increased by plantar incision 24 h after surgery. Pharmacological inhibition of ASIC3 channels with the specific toxin APETx2 or in vivo knockdown of ASIC3 subunit by small interfering RNA led to a significant reduction of postoperative spontaneous, thermal, and postural pain behaviors (spontaneous flinching, heat hyperalgesia, and weight bearing). ASIC3 appears to have an important role in deep tissue but also affects prolonged pain evoked by skin incision alone. The specific homomeric ASIC1a blocker PcTx1 has no effect on spontaneous flinching, when applied peripherally. Together, these data demonstrate a significant role for peripheral ASIC3-containing channels in postoperative pain.

Peripheral sensitization caused by insulin-like growth factor 1 contributes to pain hypersensitivity after tissue injury

Sensitization of primary afferent neurons is one of the most important components of pain hypersensitivity after tissue injury. Insulin-like growth factor 1 (IGF-1), involved in wound repair in injured tissue, also plays an important role in maintaining neuronal function. In the present study, we investigated the effect of tissue IGF-1 on nociceptive sensitivity of primary afferent neurons. Local administration of IGF-1 induced thermal and mechanical pain hypersensitivity in a dose-dependent manner, and was attenuated by IGF-1 receptor (IGF1R) inhibition. Tissue but not plasma IGF-1 levels, as determined by enzyme-linked immunosorbent assay, significantly increased after plantar incision. Immunohistochemistry revealed that IGF1R was predominantly expressed in neurons as well as in satellite glial cells in the dorsal root ganglion (DRG). Double-labeling immunohistochemistry showed that IGF1R expression colocalized with peripherin and TRPV1, but not with NF200 in DRG neurons. The IGF1R inhibitor successfully alleviated mechanical allodynia, heat hyperalgesia, and spontaneous pain behavior observed after plantar incision. Expression of phosphorylated Akt in DRG neurons significantly increased after plantar incision and was suppressed by IGF1R inhibition. These results demonstrate that increased tissue IGF-1 production sensitizes primary afferent neurons via the IGF1R/Akt pathway to facilitate pain hypersensitivity after tissue damage.Insulin-like growth factor 1 is synthesized locally after tissue injury and contributes to the sensitization of primary afferent neurons.

Role of Sigma Receptor and Neurosteroids in Pain Sensation

The sigma-1 receptor has recently been implicated in a myriad of cellular functions and biological processes. Previous studies have demonstrated that the spinal sigma-1 receptor plays a pro-nociceptive role in acute pain and that the direct activation of sigma-1 receptor enhances the nociceptive response to peripheral stimuli, which is closely associated with calcium-dependent second messenger cascades including protein kinase C (PKC). In addition, the activation of sigma-1 receptor increases PKCand protein kinase alpha (PKA)-dependent phosphorylation of the N-MethylD-aspartate (NMDA) receptor in the spinal cord, which results in the potentiation of intrathecal NMDA-evoked spontaneous pain behavior. Moreover, the blockade of spinal sigma-1 receptor suppresses the development of neuropathic pain and blocks the increase of phosphorylation of extracellular signal-regulated kinase (ERK) as well as pNR1 in the spinal cord. Recently, it was also reported that spinal neurosteroids such as pregnenolone and dehydroepiandrosterone sulfate, which are recognized as endogenous ligands for sigma-1 receptor, could produce mechanical hypersensitivity via sigma-1 receptor-mediated increase of pNR1. Collectively, these findings demonstrate that the activation of spinal sigma-1 receptor or the increase of neurosteroids is closely associated with the acute pain sensation or the development of chronic pain, and imply that sigma-1 receptor can be a new potential target for the development of analgesics.

Analgesic effects of intra-articular botulinum toxin Type B in a murine model of chronic degenerative knee arthritis pain

Objective:To evaluate the analgesic effectiveness of intra-articular botulinum toxin Type B (BoNT/B) in a murine model of chronic degenerative arthritis pain.Methods and materials:Chronic arthritis was produced in adult C57Bl6 mice by intra-articular injection of Type IV collagenase into the left knee. Following induction of arthritis, the treatment group received intra-articular BoNT/B. Arthritic control groups were treated with intra-articular normal saline or sham injections. Pain behavior testing was performed prior to arthritis, after induction of arthritis, and following treatments. Pain behavior measures included analysis of gait impairment (spontaneous pain behavior) and joint tenderness evaluation (evoked pain response). Strength was measured as ability to grasp and cling.Results:Visual gait analysis showed significant impairment of gait in arthritic mice that improved 43% after intra-articular BoNT/B, demonstrating a substantial articular analgesic effect. Joint tenderness, measured with evoked pain response scores, increased with arthritis induction and decreased 49.5% after intra-articular BoNT/B treatment. No improvement in visual gait scores or decrease in evoked pain response scores were found in the control groups receiving intra-articular normal saline or sham injections. Intra-articular BoNT/B was safe, and no systemic effects or limb weakness was noted.Conclusions:This study is the first report of intra-articular BoNT/B for analgesia in a murine model of arthritis pain. The results of this study validate prior work using intra-articular neurotoxins in murine models. Our findings show chronic degenerative arthritis pain can be quantitated in a murine model by measuring gait impairment using visual gait analysis scores (spontaneous pain behavior) and joint tenderness scores (evoked pain responses). Reduction of joint pain seen in this study is consistent with our hypothesis of inhibition of release of pain mediators by intra-articular BoNT/B, supporting further investigation of this novel approach to treatment of arthritis pain with intra-articular neurotoxins.

Delayed olfactory ensheathing cell transplants reduce nociception after dorsal root injury

Injury to cervical dorsal roots mimics the deafferentation component of brachial plexus injury in humans, with intractable neuropathic pain in the deafferented limb being a common consequence. Such lesions are generally not amenable to surgical repair. The use of olfactory ensheathing cells (OECs) for dorsal root repair, via acute transplantation, has been successful in several studies. From a clinical point of view, delayed transplantation of OECs would provide a more realistic timeframe for repair. In this study we investigated the effect of delayed OEC transplantation on functional recovery of skilled forepaw movements and amelioration of neuropathic pain, using a C7 and C8 dorsal root injury rat model previously established in our lab. We found that OEC transplantation to the dorsal horn 1week after root injury effectively attenuated neuropathic disturbances associated with dorsal root injury, including spontaneous pain behavior, tactile allodynia and thermal hyperalgesia. The sensory controls of complex, goal-oriented skilled reaching and ladder walking, however, were not improved by delayed OEC transplantation. We did not detect any significant influence of transplanted OECs on injury-induced central reorganisation and afferent sprouting. The anti-nociceptive effect mediated by OEC transplants may therefore be explained by alternative mechanisms such as modification of inflammation and astrogliosis. The significant effect of OEC transplants in mitigating neuropathic pain may be clinically useful in intractable pain syndromes arising from deafferentation. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.