Cancer pain and neuropathic pain are associated with A ß sensory neuronal plasticity in dorsal root ganglia and abnormal sprouting in lumbar spinal cord.

Evidence suggests that there are both nociceptive and neuropathic components of cancer-induced pain. We have observed that changes in intrinsic membrane properties and excitability of normally non-nociceptive Aß sensory neurons are consistent in rat models of peripheral neuropathic pain and cancer-induced pain. This has prompted a comparative investigation of the intracellular electrophysiological characteristics of sensory neurons and of the ultrastructural morphology of the dorsal horn in rat models of neuropathic pain and cancer-induced pain. Neuropathic pain model rats were induced with a polyethylene cuff implanted around a sciatic nerve. Cancer-induced pain model rats were induced with mammary rat metastasis tumour-1 rat breast cancer or MATLyLu rat prostate cancer cells implanted into the distal epiphysis of a femur. Behavioural evidence of nociception was detected using von Frey tactile assessment. Aß-fibre low threshold mechanoreceptor neurons in both cancer-induced pain and neuropathic pain models exhibited slower dynamics of action potential genesis, including a wider action potential duration and lower action potential amplitude compared to those in control animals. Enhanced excitability of Aß-fibre low threshold mechanoreceptor neurons was also observed in cancer-induced pain and neuropathic pain models. Furthermore, both cancer-induced pain and neuropathic pain models showed abundant abnormal axonal sprouting in bundles of myelinated axons in the ipsilateral spinal laminae IV and V. The patterns of changes show consistency between rat models of cancer-induced pain and neuropathic pain. These findings add to the body of evidence that animal models of cancer-induced pain and neuropathic pain share features that may contribute to the peripheral and central sensitization and tactile hypersensitivity in both pain states.

Rat model of cancer-induced bone pain: changes in nonnociceptive sensory neurons in vivo.

INTRODUCTION: Clinical data on cancer-induced bone pain (CIBP) suggest extensive changes in sensory function. In a previous investigation of an animal model of CIBP, we have observed that changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) nociceptive neurons correspond to mechanical allodynia and hyperalgesia. OBJECTIVES: To investigate the mechanisms underlying changes in nonnociceptive sensory neurons in this model, we have compared the electrophysiological properties of primary nonnociceptive sensory neurons at <1 and >2 weeks after CIBP model induction with properties in sham control animals. METHODS: Copenhagen rats were injected with 106 MAT-LyLu rat prostate cancer cells into the distal femur epiphysis to generate a model of CIBP. After von Frey tactile measurement of mechanical withdrawal thresholds, the animals were prepared for acute electrophysiological recordings of mechanically sensitive neurons in the DRG in vivo. RESULTS: The mechanical withdrawal threshold progressively decreased in CIBP model rats. At <1 week after model induction, there were no changes observed in nonnociceptive Aß-fiber DRG neurons between CIBP model rats and sham rats. However, at >2 weeks, the Aß-fiber low-threshold mechanoreceptors (LTMs) in CIBP model rats exhibited a slowing of the dynamics of action potential (AP) genesis, including wider AP duration and lower AP amplitude compared with sham rats. Furthermore, enhanced excitability of Aß-fiber LTM neurons was observed as an excitatory discharge in response to intracellular injection of depolarizing current into the soma. CONCLUSION: After induction of the CIBP model, Aß-fiber LTMs at >2 weeks but not <1 week had undergone changes in electrophysiological properties. Importantly, changes observed are consistent with observations in models of peripheral neuropathy. Thus, Aß-fiber nonnociceptive primary sensory neurons might be involved in the peripheral sensitization and tumor-induced tactile hypersensitivity in CIBP.

Differences in electrophysiological properties of functionally identified nociceptive sensory neurons in an animal model of cancer-induced bone pain.

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 Aß-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.

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.

Pain-QuILT: assessing clinical feasibility of a Web-based tool for the visual self-report of pain in an interdisciplinary pediatric chronic pain clinic.

OBJECTIVES: To evaluate clinical feasibility of the Pain-QuILT (previously known as the Iconic Pain Assessment Tool) from the perspective of adolescents with chronic pain and members of their interdisciplinary health team. The Pain-QuILT (PQ), a web-based tool that records the visual self-report of sensory pain in the form of time-stamped records, was directly compared with standard interview questions that were transformed to a paper-based tool. METHODS: Qualitative, semi-structured interviews were used to refine the PQ. Adolescents with chronic pain aged 12 to 18 years used the PQ and comparator tool (randomized order) to self-report pain before a scheduled clinic appointment, and then took part in a semi-structured interview. The health team used these pain reports (PQ and comparator) during patient appointments, and later participated in focus group interviews. Interview audio recordings were transcribed verbatim and underwent a simple line-by-line content analysis to identify key concepts. RESULTS: A total of 17 adolescents and 9 health team members completed the study. All adolescents felt that the PQ was easy to use and understand. The median time required for completion of the PQ and comparator tool was 3.3 and 3.6 minutes, respectively. Overall, 15/17 (88%) of adolescents preferred the PQ to self-report their pain versus the comparator. The health team indicated that the PQ was a clinically useful tool and identified minor barriers to implementation. DISCUSSION: Consultations with adolescents and their health team indicate that the PQ is a clinically feasible tool for eliciting detailed self-report records of the sensory experience of chronic pain.

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.

Peripheral neuropathy induces cutaneous hypersensitivity in chronically spinalized rats.

BACKGROUND/OBJECTIVES: The present study was aimed at the issue of whether peripheral nerve injury-induced chronic pain is maintained by supraspinal structures governing descending facilitation to the spinal dorsal horn, or whether altered peripheral nociceptive mechanisms sustain central hyperexcitability and, in turn, neuropathic pain. We examined this question by determining the contribution of peripheral/spinal mechanisms, isolated from supraspinal influence(s), in cutaneous hypersensitivity in an animal model of peripheral neuropathy. METHODS: Adult rats were spinalized at T8-T9; 8 days later, peripheral neuropathy was induced by implanting a 2-mm polyethylene cuff around the left sciatic nerve. Hind paw withdrawal responses to mechanical or thermal plantar stimulation were evaluated using von Frey filaments or a heat lamp, respectively. RESULTS: Spinalized rats without cuff implantation exhibited a moderate decrease in mechanical withdrawal threshold on ~day 10 (P < 0.05) and in thermal withdrawal threshold on ~day 18 (P < 0.05). However, cuff-implanted spinalized rats developed a more rapid and significant decrease in mechanical (~day 4; P < 0.001) and thermal (~day 10; P < 0.05) withdrawal thresholds that remained significantly decreased through the duration of the study. CONCLUSIONS: Our findings demonstrate an aberrant peripheral/spinal mechanism that induces and maintains thermal and to a greater degree tactile cutaneous hypersensitivity in the cuff model of neuropathic pain, and raise the prospect that altered peripheral/spinal nociceptive mechanisms in humans with peripheral neuropathy may have a pathologically relevant role in both inducing and sustaining neuropathic pain.

Peripheral drive in Aα/ß-fiber neurons is altered in a rat model of osteoarthritis: changes in following frequency and recovery from inactivation.

PURPOSE: To determine conduction fidelity of Aα/ß-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.

Understanding the information and service needs of young adults with chronic pain: perspectives of young adults and their providers.

OBJECTIVE: To qualitatively explore the information and service needs of young adults (YAs) with chronic pain to inform the development of a web-based chronic pain self-management program. METHODS: A convenience sample of YAs (n=17; aged 18 to 29 y) with chronic pain was recruited from 2 adult tertiary care multidisciplinary chronic pain clinics in Ontario. Interdisciplinary health care professionals who had worked in chronic pain for at least 1 year were also recruited from these sites. Five audiotaped focus groups were conducted, 3 for YAs and 2 for health care professionals. Transcribed data were organized into categories that reflected emerging themes. RESULTS: Findings uncovered 4 major themes: (1) pain impact, (2) pain management strategies, (3) barriers to care, and (4) service delivery recommendations. Subthemes were found under each major theme. Pain had an impact on social and emotional realms and role functioning, physical functioning, and future vocational and life goals. Pain management strategies were comprised of psychological, physical, and pharmacological approaches and development of support systems. Barriers to care were revealed at the patient, health care system, and societal levels. Finally, service delivery recommendations were divided into 2 subthemes pertaining to improved services and Internet-based programs. DISCUSSION: Participants unanimously felt that a web-based program would be an acceptable means to help improve access to services and meet the need for more information about chronic pain, strategies to manage pain symptoms, and social support to address the unique developmental needs of YAs.

Adapting the Iconic Pain Assessment Tool Version 2 (IPAT2) for adults and adolescents with arthritis pain through usability testing and refinement of pain quality icons.

OBJECTIVES: To evaluate usability and pain iconography of the Iconic Pain Assessment Tool Version 2 (IPAT2), a self-report instrument that combines word descriptors and representative images (icons) to assess pain quality, intensity, and location, among adults and adolescents with arthritis. METHODS: Adults with inflammatory arthritis and adolescents with juvenile idiopathic arthritis partook in a single, semistructured, audio-recorded interview to evaluate: (1) the concreteness (object representativeness) and semantic distance (pain representativeness) of the IPAT2 iconography; (2) participants' current pain; and (3) perceptions and likes/dislikes of the IPAT2. Quantitative data were summarized descriptively and a line-by-line coding analysis identified key concepts from interview transcripts. The criterion for icon acceptability was mean and median ratings ≥5.0 for concreteness, semantic distance, and satisfaction for describing arthritis pain. RESULTS: The sample was comprised of 15 adults (87% female, mean 57 y) and 15 adolescents (67% female, mean age 15 y). The IPAT2 was reported to be easy to use and understand, well liked, quick to complete, and perceived as potentially valuable for communicating arthritis pain to health care providers. The median time needed to complete a single pain record, after 5-minute demonstration, was 2.3 minutes and 1.4 minutes for the adults and adolescents, respectively. All pain quality icons met or exceeded the criterion for acceptability. DISCUSSION: All a priori objectives for the IPAT2 were achieved in this sample of rheumatology outpatients. With its unique blend of pain quality descriptors and representative images, the IPAT2 may importantly aid the assessment of pain in adults and adolescents with arthritis.

Lumbar facet joint compressive injury induces lasting changes in local structure, nociceptive scores, and inflammatory mediators in a novel rat model.

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-1ß. 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.

Changes in functional properties of A-type but not C-type sensory neurons in vivo in a rat model of peripheral neuropathy.

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 Aß-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 Aß-fiber low threshold mechanoreceptor neurons that might contribute to peripheral neuropathic pain.

Functional changes in muscle afferent neurones in an osteoarthritis model: implications for impaired proprioceptive performance.

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.

Excitability of Aß sensory neurons is altered in an animal model of peripheral neuropathy.

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 Aß, 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 Aß-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. Aß 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 Aß 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 Aß sensory neurons may thus contribute to allodynia and spontaneous pain following peripheral nerve injury in humans.

Neuropathic pain as a process: reversal of chronification in an animal model.

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 NK(1) 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.

The selective neuronal nitric oxide synthase inhibitor 7-nitroindazole has acute analgesic but not cumulative effects in a rat model of peripheral neuropathy.

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.

Progesterone prevents development of neuropathic pain in a rat model: Timing and duration of treatment are critical.

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.

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.

Changes in Abeta non-nociceptive primary sensory neurons in a rat model of osteoarthritis pain.

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. Abeta-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 Adelta-fiber nociceptors. CONCLUSION: Thus, at one month after induction of the OA model Abeta-fiber low threshold mechanoreceptors but not C- or Adelta-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 Abeta-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.

Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model.

OBJECTIVE: To verify the biologic links between progressive cellular and structural alterations within knee joint components and development of symptomatic chronic pain that are characteristic of osteoarthritis (OA), and to investigate the molecular basis of alterations in nociceptive pathways caused by OA-induced pain. METHODS: An animal model of knee joint OA pain was generated by intraarticular injection of mono-iodoacetate (MIA) in Sprague-Dawley rats, and symptomatic pain behavior tests were performed. 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 histologic and immunohistologic analysis, microscopic examination, and microfocal computed tomography. Progressive changes in the dynamic interrelationships between peripheral knee joint tissue and central components of nociceptive pathways caused by OA-induced pain were examined by investigating cytokine production and expression in sensory neurons of the dorsal root ganglion and spinal cord. RESULTS: We observed that structural changes in components of the peripheral knee joint correlate with alterations in the central compartments (dorsal root ganglia and the spinal cord) and symptomatic pain assessed by behavioral hyperalgesia. Our comparative gene expression studies revealed that the pain pathways in MIA-induced knee OA may overlap, at least in part, with neuropathic pain mechanisms. Similar results were also observed upon destabilization of the knee joint in the anterior cruciate ligament transection and destabilization of the medial meniscus models of OA. CONCLUSION: Our results indicate that MIA-induced joint degeneration in rats generates an animal model that is suitable for mechanistic and pharmacologic studies on nociceptive pain pathways caused by OA, and 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.