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1.  Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy 
Experimental neurology  2008;214(2):219-228.
Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague–Dawley rats 2–6 weeks after cuff implantation we found that elevated discharge rate of single lumbar (L3–4) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons ~40% (n=18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by ~60% (n=19; P<0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. Furthermore, in cuff-implanted rats WDR neurons (n=5) responded to mechanical cutaneous stimulation with an exaggerated afterdischarge which was reversed entirely by proximal nerve conduction block. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synaptically-mediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy.
doi:10.1016/j.expneurol.2008.08.003
PMCID: PMC5132624  PMID: 18773893 CAMSID: cams421
Neuropathic pain; Primary afferent; Ectopic discharge; Nerve block; Lidocaine; Spinal cord; Central sensitization; Dorsal horn
2.  Sensory and vascular changes in a rat monoarthritis model: prophylactic and therapeutic effects of meloxicam 
Objective and design
The objective of this study was to determine the ability of meloxicam prophylaxis and therapy to blunt the effect of complete Freund’s adjuvant (CFA) induced monoarthritis.
Materials and methods
First the validity of this animal model was established by examining joint changes at multiple levels after injecting CFA into the tibio-tarsal joint. Next, meloxicam (5 mg/kg) or vehicle was administered on days 0–7 (prophylactic) and on days 7–16 (therapeutic) in separate groups of animals.
Results
The CFA-injected joint demonstrated hallmark histological and structural changes such as pannus formation, bone remodeling, cartilage erosion and immune cell infiltration. Both prophylactic and therapeutic treatment with meloxicam effectively reduced swelling (ankle circumference), oedema and extravasation of Evans blue dye in the affected joint. Moreover, meloxicam reduced loss in range of motion and also reduced mechanical stimulus evoked pain scores. Notably, these effects persisted after discontinuing drug treatment.
Conclusion
The present study provides a unique comparison of prophylactic versus therapeutic effects of meloxicam in the CFA-induced model of monoarthritis.
doi:10.1007/s00011-010-0179-3
PMCID: PMC5132625  PMID: 20349327 CAMSID: cams419
Animal model; Inflammatory joint disease; Joint pain; Range of motion; CFA; Rheumatoid arthritis
3.  Physiological evidence of a postsynaptic inhibition of the tail flick reflex by a cannabinoid receptor agonist 
European journal of pharmacology  2008;602(1):36-40.
Current evidence indicates that cannabinoids are antinociceptive and this effect is in part mediated by spinal mechanisms. Anatomical studies have localized cannabinoid CB1 receptors to pre- and postsynaptic sites within the spinal cord. However, behavioural tests have not clearly indicated the relative importance of each of these sites. In this study, the tail flick test was used as a model of acute pain in the rat to determine the site of action of WIN 55,212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), a synthetic cannabinoid receptor agonist. WIN 55,212-2 (3 mg/kg, i.p.) increased the latency of tail withdrawal from a noxious radiant heat source, indicating it is antinociceptive in this model. Using the same paradigm, WIN 55,212-2 was then tested against the synaptically-induced nociceptive hypersensitivity in response to noxious thermal stimulation of the tail (hot water tail immersion). WIN 55,212-2 blocked this hypersensitivity, confirming a spinal site of action of the cannabinoid receptor agonist. Further, WIN 55,212-2 blocked the nociceptive hypersensitivity induced by intrathecal administration of substance P. As substance P acts on postsynaptic tachykinin NK1 receptors in the dorsal horn of the spinal cord, the data are interpreted to suggest that WIN 55,212-2 expressed its anti-hypersensitivity effects at least partially via a postsynaptic site of action; the data do not rule out a presynaptic site of action. This study suggests that cannabinoids may induce analgesia via a postsynaptic site of action in the spinal cord, as well as the possibility that they may interact with substance P signaling.
doi:10.1016/j.ejphar.2008.10.061
PMCID: PMC5130341  PMID: 19027734 CAMSID: cams417
Cannabinoid; WIN 55,212-2; Nociception; Analgesic; Tail flick test; Spinal cord (Rat)
4.  Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat 
European journal of pharmacology  2004;507(1-3):99-105.
Although a wide assortment of agents is currently available for the treatment of depression, this disorder remains poorly managed in a large proportion of patients. Traditional antidepressant treatments target the biogenic amine systems. However, a growing body of evidence is implicating the involvement of neuropeptides in depression, especially the neurokinin substance P. This study evaluated the effects of selective antagonists of the tachykinin NK1, NK2, and NK3 receptors in the forced swim test, a commonly used screen for antidepressants. Rats were given CP-96,345 (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, or SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, antagonists of the NK1, NK2, and NK3 receptors, respectively, at doses of 2.5, 5, and 10 mg/kg, intraperitoneally (i.p.). The time of immobility during the forced swim test was used as an indicator of antidepressant activity of the antagonists. All antagonists decreased immobility times. CP-96,345 and SR 142801 showed dose-related effects; SR 48968 had its maximum effect at 2.5 mg/kg. The magnitude of the effects of the neurokinin receptor antagonists was approximately the same as that of amitriptyline and desipramine, two traditional antidepressants, both given at 10 mg/kg, i.p. This study provides comparative data on the relative effectiveness of NK1, NK2, and NK3 receptor antagonists in this screen for antidepressant drug activity.
doi:10.1016/j.ejphar.2004.11.024
PMCID: PMC5127697  PMID: 15659299 CAMSID: cams410
Forced swim test; Depression; Neurokinin receptor antagonist; CP-96,345; SR 48968; SR 142801
5.  Lumbar Facet Joint Compressive Injury Induces Lasting Changes in Local Structure, Nociceptive Scores, and Inflammatory Mediators in a Novel Rat Model 
Pain Research and Treatment  2012;2012:127636.
Objective. To develop a novel animal model of persisting lumbar facet joint pain. Methods. Sprague Dawley rats were anaesthetized and the right lumbar (L5/L6) facet joint was exposed and compressed to ~1 mm with modified clamps applied for three minutes; sham-operated and naïve animals were used as control groups. After five days, animals were tested for hind-paw sensitivity using von Frey filaments and axial deep tissue sensitivity by algometer on assigned days up to 28 days. Animals were sacrificed at selected times for histological and biochemical analysis. Results. Histological sections revealed site-specific loss of cartilage in model animals only. Tactile hypersensitivity was observed for the ipsi- and contralateral paws lasting 28 days. The threshold at which deep tissue pressure just elicited vocalization was obtained at three lumbar levels; sensitivity at L1 > L3/4 > L6. Biochemical analyses revealed increases in proinflammatory cytokines, especially TNF-α, IL-1α, and IL-1β. Conclusions. These data suggest that compression of a facet joint induces a novel model of local cartilage loss accompanied by increased sensitivity to mechanical stimuli and by increases in inflammatory mediators. This new model may be useful for studies on mechanisms and treatment of lumbar facet joint pain and osteoarthritis.
doi:10.1155/2012/127636
PMCID: PMC3395270  PMID: 22966427
6.  Differences in electrophysiological properties of functionally identified nociceptive sensory neurons in an animal model of cancer-induced bone pain 
Molecular Pain  2016;12:1744806916628778.
Background
Bone cancer pain is often severe, yet little is known about mechanisms generating this type of chronic pain. While previous studies have identified functional alterations in peripheral sensory neurons that correlate with bone tumours, none has provided direct evidence correlating behavioural nociceptive responses with properties of sensory neurons in an intact bone cancer model.
Results
In a rat model of prostate cancer-induced bone pain, we confirmed tactile hypersensitivity using the von Frey test. Subsequently, we recorded intracellularly from dorsal root ganglion neurons in vivo in anesthetized animals. Neurons remained connected to their peripheral receptive terminals and were classified on the basis of action potential properties, responses to dorsal root stimulation, and to mechanical stimulation of the respective peripheral receptive fields. Neurons included C-, Aδ-, and Aβ-fibre nociceptors, identified by their expression of substance P. We suggest that bone tumour may induce phenotypic changes in peripheral nociceptors and that these could contribute to bone cancer pain.
Conclusions
This work represents a significant technical and conceptual advance in the study of peripheral nociceptor functions in the development of cancer-induced bone pain. This is the first study to report that changes in sensitivity and excitability of dorsal root ganglion primary afferents directly correspond to mechanical allodynia and hyperalgesia behaviours following prostate cancer cell injection into the femur of rats. Furthermore, our unique combination of techniques has allowed us to follow, in a single neuron, mechanical pain-related behaviours, electrophysiological changes in action potential properties, and dorsal root substance P expression. These data provide a more complete understanding of this unique pain state at the cellular level that may allow for future development of mechanism-based treatments for cancer-induced bone pain.
doi:10.1177/1744806916628778
PMCID: PMC4994860  PMID: 27030711
Bone cancer; pain; primary afferent; dorsal root ganglion; electrophysiology; behaviour; prostate cancer
7.  Pain-QuILT: Clinical Feasibility of a Web-Based Visual Pain Assessment Tool in Adults With Chronic Pain 
Background
Chronic pain is a prevalent and debilitating problem. Accurate and timely pain assessment is critical to pain management. In particular, pain needs to be consistently tracked over time in order to gauge the effectiveness of different treatments. In current clinical practice, paper-based questionnaires are the norm for pain assessment. However, these methods are not conducive to capturing or tracking the complex sensations of chronic pain. Pain-QuILT (previously called the Iconic Pain Assessment Tool) is a Web-based tool for the visual self-report and tracking of pain (quality, intensity, location, tracker) in the form of time-stamped records. It has been iteratively developed and evaluated in adolescents and adults with chronic pain, including usability testing and content validation. Clinical feasibility is an important stepping-stone toward widespread implementation of a new tool. Our group has demonstrated Pain-QuILT clinical feasibility in the context of a pediatric chronic pain clinic. We sought to extend these findings by evaluating Pain-QuILT clinical feasibility from the perspective of adults with chronic pain, in comparison with standard paper-based methods (McGill Pain Questionnaire [MPQ] and Brief Pain Inventory [BPI]).
Objective
The goal of our study was to assess Pain-QuILT for (1) ease of use, (2) time for completion, (3) patient preferences, and (4) to explore the patterns of self-reported pain across the Pain-QuILT, MPQ, and BPI.
Methods
Participants were recruited during a scheduled follow-up visit at a hospital-affiliated pain management and physical rehabilitation clinic in southwestern Ontario. Participants self-reported their current pain using the Pain-QuILT, MPQ, and BPI (randomized order). A semistructured interview format was used to capture participant preferences for pain self-report.
Results
The sample consisted of 50 adults (54% female, 27/50) with a mean age of 50 years. Pain-QuILT was rated as significantly easier to use than both the MPQ and BPI (P<.01) and was also associated with the fewest difficulties in completion. On average, the time to complete each tool was less than 5 minutes. A majority of participants (58%, 29/50) preferred Pain-QuILT for reporting their pain over alternate methods (16%, 8/50 for MPQ; 14%, 7/50 for BPI; 12%, 6/50 for “other”). The most commonly chosen pain descriptors on MPQ were matched with Pain-QuILT across 91% of categories. There was a moderate-to-high correlation between Pain-QuILT and BPI scores for pain intensity (r=.70, P<.01).
Conclusions
The results of this clinical feasibility study in adults with chronic pain are consistent with our previously published pediatric findings. Specifically, data indicate that Pain-QuILT is (1) easy to use, (2) quick to complete, (3) preferred by a majority of patients, and (4) correlated as expected with validated pain measures. As a digital, patient-friendly method of assessing and tracking pain, we conclude that Pain-QuILT has potential to add significant value as one standard component of chronic pain management.
doi:10.2196/jmir.3292
PMCID: PMC4034112  PMID: 24819478
chronic pain; assessment tool; Internet; clinical feasibility
8.  Peripheral drive in Aα/β-fiber neurons is altered in a rat model of osteoarthritis: changes in following frequency and recovery from inactivation 
Journal of Pain Research  2013;6:207-221.
Purpose
To determine conduction fidelity of Aα/β-fiber low threshold mechanoreceptors in a model of osteoarthritis (OA).
Methods
Four weeks after cutting the anterior cruciate ligament and removing the medial meniscus to induce the model, in vivo intracellular recordings were made in ipsilateral L4 dorsal root ganglion neurons. L4 dorsal roots were stimulated to determine the refractory interval and the maximum following frequency of the evoked action potential (AP). Neurons exhibited two types of response to paired pulse stimulation.
Results
One type of response was characterized by fractionation of the evoked AP into an initial nonmyelinated-spike and a later larger-amplitude somatic-spike at shorter interstimulus intervals. The other type of response was characterized by an all-or-none AP, where the second evoked AP failed altogether at shorter interstimulus intervals. In OA versus control animals, the refractory interval measured in paired pulse testing was less in all low threshold mechanoreceptors. With train stimulation, the maximum rising rate of the nonmyelinated-spike was greater in OA nonmuscle spindle low threshold mechanoreceptors, possibly due to changes in fast kinetics of currents. Maximum following frequency in Pacinian and muscle spindle neurons was greater in model animals compared to controls. Train stimulation also induced an inactivation and fractionation of the AP in neurons that showed fractionation of the AP in paired pulse testing. However, with train stimulation this fractionation followed a different time course, suggesting more than one type of inactivation.
Conclusion
The data suggest that joint damage can lead to changes in the fidelity of AP conduction of large diameter sensory neurons, muscle spindle neurons in particular, arising from articular and nonarticular tissues in OA animals compared to controls. These changes might influence peripheral drive of spinal excitability and plasticity, thus contributing to OA sensory abnormalities, including OA pain.
doi:10.2147/JPR.S40445
PMCID: PMC3650889  PMID: 23671396
dorsal root ganglion; repetitive firing; peripheral drive; electrophysiology; conduction failure; adaptation
9.  Changes in functional properties of A-type but not C-type sensory neurons in vivo in a rat model of peripheral neuropathy 
Journal of Pain Research  2012;5:175-192.
Background
The aim of this study was to compare primary sensory neurons in controls and in an animal neuropathic pain model in order to understand which types of neurons undergo changes associated with peripheral neuropathy. On the basis of intracellular recordings in vivo from somata, L4 sensory dorsal root ganglion neurons were categorized according to action potential configuration, conduction velocity, and receptive field properties to mechanical stimuli.
Methods
Intracellular recordings were made from functionally identified dorsal root ganglion neurons in vivo in the Mosconi and Kruger animal model of peripheral neuropathic pain.
Results
In this peripheral neuropathy model, a specific population of Aβ-fiber low threshold mechanoreceptor neurons, which respond normally to innocuous mechanical stimuli, exhibited differences in action potential configuration and conduction velocity when compared with control animals. No abnormal conduction velocity, action potential shapes, or tactile sensitivity of C-fiber neurons were encountered.
Conclusion
This study provides evidence for defining a potential role of Aβ-fiber low threshold mechanoreceptor neurons that might contribute to peripheral neuropathic pain.
doi:10.2147/JPR.S26367
PMCID: PMC3392709  PMID: 22792004
peripheral neuropathy; neuropathic pain; primary sensory neuron; dorsal root ganglion; action potential configuration; animal model; in vivo recording
10.  Evaluation of the Iconic Pain Assessment Tool by a heterogeneous group of people in pain 
The Iconic Pain Assessment Tool (IPAT) is a novel web-based instrument for the self-report of pain quality, intensity and location in the form of a permanent diary. Originally designed for people with central poststroke pain, the tool is being adapted for a larger, more diverse patient population. The present study aimed to collect evaluative feedback on the IPAT from a heterogeneous sample of individuals with chronic pain. The specific study aims were to evaluate participant comfort with the tool including enjoyment, ease of use and comfort with the electronic medium; to assess perceived value of the tool for communicating pain quality, intensity and location; to gauge participant intent to share their pain diaries with others and use the tool on a regular basis to track their pain over time; to assess the perceived descriptiveness of current IPAT icons and the numerical rating scale; and to identify strengths and weaknesses of the tool to refine the existing prototype.
Written and verbal feedback from individuals with a variety of chronic pain conditions (n=23) were collected in the context of these objectives. Overall, the IPAT was positively endorsed by this heterogeneous sample of people in pain. The authors concluded that the IPAT is a user-friendly instrument that has the potential to help people express, document and share their personal experience with chronic pain.
PMCID: PMC3052402  PMID: 21369536
Chronic pain; Consumer driven; Pain diary; Pain self-assessment; Self-report; Web-based instrument
11.  Neuropathic pain as a process: reversal of chronification in an animal model 
Journal of Pain Research  2011;4:315-323.
Peripheral neuropathic pain arises from trauma to sensory nerves. Other types of acute neurotrauma such as stroke and spinal cord injury are treated immediately, largely to prevent secondary damage. To pursue the possibility that neuropathic pain may also be amenable to early treatment, a rat model of neuropathic pain was induced using a 2-mm polyethylene cuff implanted around one sciatic nerve. Within 24 hours, hypersensitivity to von Frey hair stimulation appeared, as indicated by decreased paw withdrawal thresholds. When the cuff was removed 24 hours after implantation, readings returned to pre-implantation levels starting as early as day 18. When the cuff was removed after 4 days, there was a period of initial hypersensitivity, and then an increase toward baseline at two time points near the end of the study; therefore, only a partial recovery toward pre-implantation values occurred. Having established that a temporal reversal can occur, the next step examined possible pharmacological reversal. The tachykinin NK1 receptor antagonist, CP-96,345, produced a minor increase in withdrawal thresholds in animals with the cuff left permanently implanted. To determine the effect of early and repeated administration of CP-96,345, it was given daily on days 1–4. The cuff was removed on day 4. Six days later, readings showed reversal of tactile hypersensitivity. We suggest that persistent neuropathic pain occurs from processes that develop over several hours and days, and that some of these processes may be prevented by early medical intervention. Thus, nerve injury in the context of chronic neuropathic pain should be treated in a similar manner to nerve injury resulting from stroke, spinal cord injury, and other types of neurotrauma. We suggest that effective medical intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating pain that may be refractory to later therapies.
doi:10.2147/JPR.S17882
PMCID: PMC3191931  PMID: 22003305
neurotrauma; neuroplasticity; nerve injury; neuropathy; chronic pain; tactile hypersensitivity
12.  Progesterone prevents development of neuropathic pain in a rat model: Timing and duration of treatment are critical 
Journal of Pain Research  2011;4:91-101.
Background:
Progesterone is emerging as an important protective agent against various injuries to the nervous system. Neuroprotective and remyelinating effects have been documented for this neurosteroid, which is synthesized by, and acts on, the central and peripheral nervous systems. Neuropathic pain is a severe, persistent condition that is generally resistant to treatment, and poses major personal, social, and economic burdens. The purpose of this study was to determine if single-dose or repeated progesterone administration would alleviate tactile hypersensitivity in a rat model of neuropathic pain, and to determine if early versus late initiation of treatment has an effect on the outcome.
Methods:
Rats were unilaterally implanted with a polyethylene cuff around the sciatic nerve, and sensitivity to von Frey filament stimulation was measured over approximately 12 weeks.
Results:
Rats given progesterone starting one hour after cuff implantation, and daily until day 4, exhibited tactile hypersensitivity similar to that of vehicle-treated rats for the duration of the study. When progesterone was started one hour after cuff implantation and given daily until day 10, rats exhibited no tactile hypersensitivity in the later part of the study, after treatment had stopped. When progesterone treatment was initiated at 20 days, once the model had been fully established, and given daily for 4 or even 11 days, no differences in withdrawal thresholds were observed compared with controls. Progesterone did not have any effect on withdrawal thresholds when given as a single dose, as measured at 30, 60 and 90 minutes after administration.
Conclusion:
These results indicate that progesterone, when administered immediately after nerve injury, and for a sufficient period of time, can prevent the development of neuropathic pain, and may offer new strategies for the treatment of this highly debilitating condition.
doi:10.2147/JPR.S17009
PMCID: PMC3085268  PMID: 21559355
progesterone; neurosteroid; neuropathic pain; peripheral neuropathy; recovery; neuroprotection
13.  The selective neuronal nitric oxide synthase inhibitor 7-nitroindazole has acute analgesic but not cumulative effects in a rat model of peripheral neuropathy 
Journal of Pain Research  2011;4:85-90.
Chronic neuropathic pain that may arise from various nerve injuries or insults remains notoriously difficult to manage. The neuronal isoform of the enzyme nitric oxide synthase (nNOS) has been shown to be involved in the spinal transmission of nociception in animal models of chronic pain. The aim of this study is to evaluate the effect of single dose and repeated administration of a selective nNOS inhibitor. Rats were unilaterally implanted with a 2-mm polyethylene cuff around the sciatic nerve. Paw withdrawal thresholds were measured using von Frey filament stimulation. Rats were given 10, 20, or 30 mg/kg of 7-nitroindazole (7-NI), or vehicle, on days 2, 5, and 7 after model induction, respectively. Paw withdrawal thresholds were measured before and at 30 and 60 min after injection. 7-NI significantly increased paw withdrawal thresholds at 60 min at the 20 and 30 mg/kg dosages. In the second part of this study, rats were given 20 mg/kg 7-NI daily for five days starting immediately after cuff implantation (days 0 to 4), and the cuff was removed on day 4. Withdrawal thresholds were measured intermittently over a 24-day observation period. No differences in withdrawal thresholds were observed between drug and vehicle-treated rats. Therefore, early and repeated administration of 7-NI did not affect the development or progression of the model. In conclusion, inhibition of nNOS had an analgesic but not a pre-emptive effect in this model of peripheral neuropathic pain.
doi:10.2147/JPR.S17007
PMCID: PMC3085267  PMID: 21559354
neuronal nitric oxide synthase; nitric oxide; 7-nitroindazole; neuropathic pain; peripheral nerve injury; nociception
14.  A systematic review of the effectiveness of knowledge translation interventions for chronic noncancer pain management 
BACKGROUND:
Reliable evidence detailing effective treatments and management practices for chronic noncancer pain exists. However, little is known about which knowledge translation (KT) interventions lead to the uptake of this evidence in practice.
OBJECTIVES:
To conduct a systematic review of the effectiveness of KT interventions for chronic noncancer pain management.
METHODS:
Comprehensive searches of electronic databases, the gray literature and manual searches of journals were undertaken. Randomized controlled trials, controlled clinical trials and controlled before-and-after studies of KT interventions were included. Data regarding interventions and primary outcomes were categorized using a standard taxonomy; a risk-of-bias approach was adopted for study quality. A narrative synthesis of study results was conducted.
RESULTS:
More than 8500 titles and abstracts were screened, with 230 full-text articles reviewed for eligibility. Nineteen studies were included, of which only a small proportion were judged to be at low risk of bias. Interactive KT education for health care providers has a positive effect on patients’ function, but its benefits for other health provider- and patient-related outcomes are inconsistent. Interactive education for patients leads to improvements in knowledge and function. Little research evidence supports the effectiveness of structural changes in health systems and quality improvement processes or coordination of care.
CONCLUSIONS:
KT interventions incorporating interactive education in chronic noncancer pain led to positive effects on patients’ function and knowledge about pain. Future studies should provide implementation details and use consistent theoretical frameworks to better estimate the effectiveness of such interventions.
PMCID: PMC3917804  PMID: 24308029
Chronic pain; Education; Knowledge translation; Systematic review
15.  iCanCope with Pain™: User-centred design of a web- and mobile-based self-management program for youth with chronic pain based on identified health care needs 
Chronic pain self-management involves providing patients with knowledge, coping strategies and social support that help them to manage their pain. This type of intervention has been shown to be useful in treating chronic pain; however, many eligible chronic pain patients never receive such treatment due to limited accessibility and high cost. The use of Internet-based cognitive behavioural therapy has the potential to change this. In this study, the authors report their progress in the development of an Internet- and smartphone-based application for chronic pain self-management.
BACKGROUND:
While there are emerging web-based self-management programs for children and adolescents with chronic pain, there is currently not an integrated web- and smartphone-based app that specifically addresses the needs of adolescents with chronic pain.
OBJECTIVES:
To conduct a needs assessment to inform the development of an online chronic pain self-management program for adolescents, called iCanCope with Pain™.
METHODS:
A purposive sample of adolescents (n=23; 14 to 18 years of age) was recruited from two pediatric chronic pain clinics in Ontario. Interdisciplinary health care providers were also recruited from these sites. Three focus groups were conducted with adolescents (n=16) and one with pediatric health care providers (n=7). Individual adolescent interviews were also conducted (n=7).
RESULTS:
Qualitative analysis uncovered four major themes: pain impact; barriers to care; pain management strategies; and transition to adult care. Pain impacted social, emotional, physical and role functioning, as well as future goals. Barriers to care were revealed at the health care system, patient and societal levels. Pain management strategies included support systems, and pharmacological, physical and psychological approaches. Transition subthemes were: disconnect between pediatric and adult systems; skills development; parental role; and fear/anxiety. Based on these identified needs, the iCanCope with Pain™ architecture will include the core theory-based functionalities of: symptom self-monitoring; personalized goal setting; pain coping skills training; peer-based social support; and chronic pain education.
CONCLUSIONS:
The proposed iCanCope with Pain™ program aims to address the self-management needs of adolescents with chronic pain by improving access to disease information, strategies to manage symptoms and social support.
PMCID: PMC4197753  PMID: 25000507
Adolescent; Chronic pain; E-health; Mobile-health; Needs assessment; Self-management
16.  The need for knowledge translation in chronic pain 
One in five Canadians suffers from some form of persistent or chronic pain. The impact on individual lives, families and friends, the health services sector and the economy is huge. Reliable evidence is available that the burden of persistent pain can be markedly reduced when available knowledge is applied. Bridging the quality chasm between chronic pain and the care process will require a unique confluence of opinion from all stakeholders committed within a focused community of practice to address the impact of pain. Various levels of success in this regard have been demonstrated when there is exchange, synthesis and ethically sound application of research findings within a complex set of interactions among researchers and knowledge users. It is now critical to accelerate the capture of the benefits of research for Canadians through improved health, more effective and responsive services and products, and a strengthened health care system to bring about health reform and health care reform across Canada as it pertains to the one in five Canadians living with chronic, disabling pain. The overarching outcome of such an initiative needs to be promoted to sustain a balanced portfolio of curiosity-and needs-based research, which along with existing knowledge, can be mobilized and applied for the benefit of Canadians, the health care system and the economy.
PMCID: PMC2799315  PMID: 19225603
Chronic disease management; Chronic pain; Knowledge exchange; Organizational change; Research into practice; Research utilization
17.  Central poststroke pain: An abstruse outcome 
Central poststroke pain (CPSP), formerly known as thalamic pain syndrome of Déjerine and Roussy, is a central neuropathic pain occurring in patients affected by stroke. It is one manifestation of central pain, which is broadly defined as central neuropathic pain caused by lesions or dysfunction in the central nervous system. Thalamic pain was first described 100 years ago by Déjerine and Roussy and has been described as “among the most spectacular, distressing, and intractable of pain syndromes”. CPSP is characterized by constant or intermittent pain and is associated with sensory abnormalities, particularly of thermal sensation. While the pain is frequently described as burning, scalding, or burning and freezing, other symptoms are usually vague and hard to characterize, making an early diagnosis particularly difficult. In fact, those who develop CPSP may no longer be under the care of health care professionals when their symptoms begin to manifest, resulting in misdiagnosis or a significant delay before treatment begins. Diagnosis is further complicated by cognitive and speech limitations that may occur following stroke, as well as by depression, anxiety and sleep disturbances. Patients may also exhibit spontaneous dysesthesia and the stimulus-evoked sensory disturbances of dysesthesia, allodynia and hyperalgesia. The present study offers a historical reference point for future clinical and basic research into this elusive type of debilitating pain.
PMCID: PMC2670809  PMID: 18301815
Allodynia; Central neuropathic pain; Hypersensitivity; Poststroke pain; Stroke; Thalamic syndrome
19.  Functional Changes in Muscle Afferent Neurones in an Osteoarthritis Model: Implications for Impaired Proprioceptive Performance 
PLoS ONE  2012;7(5):e36854.
Background
Impaired proprioceptive performance is a significant clinical issue for many who suffer osteoarthritis (OA) and is a risk factor for falls and other liabilities. This study was designed to evaluate weight-bearing distribution in a rat model of OA and to determine whether changes also occur in muscle afferent neurones.
Methodology/Principal Findings
Intracellular recordings were made in functionally identified dorsal root ganglion neurones in acute electrophysiological experiments on the anaesthetized animal following measurements of hind limb weight bearing in the incapacitance test. OA rats but not naïve control rats stood with less weight on the ipsilateral hind leg (P = 0.02). In the acute electrophysiological experiments that followed weight bearing measurements, action potentials (AP) elicited by electrical stimulation of the dorsal roots differed in OA rats, including longer AP duration (P = 0.006), slower rise time (P = 0.001) and slower maximum rising rate (P = 0.03). Depolarizing intracellular current injection elicited more APs in models than in naïve muscle afferent neurones (P = 0.01) indicating greater excitability. Axonal conduction velocity in model animals was slower (P = 0.04).
Conclusions/Significance
The present study demonstrates changes in hind limb stance accompanied by changes in the functional properties of muscle afferent neurones in this derangement model of OA. This may provide a possible avenue to explore mechanisms underlying the impaired proprioceptive performance and perhaps other sensory disorders in people with OA.
doi:10.1371/journal.pone.0036854
PMCID: PMC3351471  PMID: 22606297
20.  Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy 
BMC Neuroscience  2012;13:15.
Background
Causes of neuropathic pain following nerve injury remain unclear, limiting the development of mechanism-based therapeutic approaches. Animal models have provided some directions, but little is known about the specific sensory neurons that undergo changes in such a way as to induce and maintain activation of sensory pain pathways. Our previous studies implicated changes in the Aβ, normally non-nociceptive neurons in activating spinal nociceptive neurons in a cuff-induced animal model of neuropathic pain and the present study was directed specifically at determining any change in excitability of these neurons. Thus, the present study aimed at recording intracellularly from Aβ-fiber dorsal root ganglion (DRG) neurons and determining excitability of the peripheral receptive field, of the cell body and of the dorsal roots.
Methods
A peripheral neuropathy was induced in Sprague Dawley rats by inserting two thin polyethylene cuffs around the right sciatic nerve. All animals were confirmed to exhibit tactile hypersensitivity to von Frey filaments three weeks later, before the acute electrophysiological experiments. Under stable intracellular recording conditions neurons were classified functionally on the basis of their response to natural activation of their peripheral receptive field. In addition, conduction velocity of the dorsal roots, configuration of the action potential and rate of adaptation to stimulation were also criteria for classification. Excitability was measured as the threshold to activation of the peripheral receptive field, the response to intracellular injection of depolarizing current into the soma and the response to electrical stimulation of the dorsal roots.
Results
In control animals mechanical thresholds of all neurons were within normal ranges. Aβ DRG neurons in neuropathic rats demonstrated a mean mechanical threshold to receptive field stimulation that were significantly lower than in control rats, a prolonged discharge following this stimulation, a decreased activation threshold and a greater response to depolarizing current injection into the soma, as well as a longer refractory interval and delayed response to paired pulse electrical stimulation of the dorsal roots.
Conclusions
The present study has demonstrated changes in functionally classified Aβ low threshold and high threshold DRG neurons in a nerve intact animal model of peripheral neuropathy that demonstrates nociceptive responses to normally innocuous cutaneous stimuli, much the same as is observed in humans with neuropathic pain. We demonstrate further that the peripheral receptive fields of these neurons are more excitable, as are the somata. However, the dorsal roots exhibit a decrease in excitability. Thus, if these neurons participate in neuropathic pain this differential change in excitability may have implications in the peripheral drive that induces central sensitization, at least in animal models of peripheral neuropathic pain, and Aβ sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.
doi:10.1186/1471-2202-13-15
PMCID: PMC3292996  PMID: 22289651
Neuropathic pain; Primary afferent neuron; Hyperexcitability; Ectopic discharge; Muscle spindle neuron; Dorsal root ganglion
21.  Alteration of Sensory Neurons and Spinal Response To An Experimental Osteoarthritis Pain Model 
Arthritis and rheumatism  2010;62(10):2995-3005.
OBJECTIVE
(i) To verify the biological links between progressive cellular and structural alterations within knee joint components and development of symptomatic chronic pain that are characteristic of osteoarthritis (OA). (ii) To investigate the molecular basis of alterations in nociceptive pathways caused by OA-induced pain.
METHODS
An animal model for knee joint OA pain was generated by intra-articular injection of monosodium iodoacetate (MIA) in Sprague Dawley rats followed by symptomatic behavioral pain tests. The corroborating relationships between development of OA with accompanying pain responses and gradual alterations in cellular and structural knee joint components (i.e., cartilage, synovium, meniscus, subchondral bone) were examined by histology, immunohistology, microscopic examination and μCT imaging. Progressive changes in the dynamic interrelationships between peripheral knee joint tissues and central components of nociceptive pathways by OA-induced pain were examined by focusing on cytokine production and expression in sensory neurons of the dorsal root ganglion and spinal cord.
RESULTS
Our results indicate that intra-articular injection of MIA-induced joint degeneration in rats generates an animal model that is suitable for mechanistic and pharmacological studies on nociceptive pain pathways caused by OA. Our results provide key in vivo evidence that OA pain is caused by central sensitization through communication between peripheral OA nociceptors and the central sensory system. Furthermore, our data suggest a mechanistic overlap between OA-induced pain and neuropathic pain.
doi:10.1002/art.27608
PMCID: PMC2952041  PMID: 20556813
22.  Changes in Aβ non-nociceptive primary sensory neurons in a rat model of osteoarthritis pain 
Molecular Pain  2010;6:37.
Background
Pain is a major debilitating factor in osteoarthritis (OA), yet few mechanism-based therapies are available. To address the need to understand underlying mechanisms the aim of the present study was to determine changes in sensory neurons in an animal model of OA pain.
Results
The model displayed typical osteoarthritis pathology characterized by cartilage degeneration in the knee joint and also manifested knee pathophysiology (edema and increased vasculature permeability of the joint) and altered nociception of the affected limb (hind paw tenderness and knee articulation-evoked reduction in the tail flick latency). Neurons included in this report innervated regions throughout the entire hind limb. Aβ-fiber low threshold mechanoreceptors exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and slower maximum rising rate, and muscle spindle neurons were the most affected subgroup. Only minor AP configuration changes were observed in either C- or Aδ-fiber nociceptors.
Conclusion
Thus, at one month after induction of the OA model Aβ-fiber low threshold mechanoreceptors but not C- or Aδ-fiber nociceptors had undergone changes in electrophysiological properties. If these changes reflect a change in functional role of these neurons in primary afferent sensory processing, then Aβ-fiber non-nociceptive primary sensory neurons may be involved in the pathogenesis of OA pain. Further, it is important to point out that the patterns of the changes we observed are consistent with observations in models of peripheral neuropathy but not models of peripheral inflammation.
doi:10.1186/1744-8069-6-37
PMCID: PMC2908067  PMID: 20594346
23.  Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis 
Molecular Pain  2009;5:57.
Background
Clinical data on osteoarthritis (OA) suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons.
Results
At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG) neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis.
Conclusion
These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.
doi:10.1186/1744-8069-5-57
PMCID: PMC2761878  PMID: 19785765

Results 1-25 (27)