Prescribing Time in Nature for Human Health and Well-Being: Study Protocol for Tailored Park Prescriptions.

Background: eHealth technologies offer an efficient method to integrate park prescriptions into clinical practice by primary health care (PHC) providers to help patients improve their health via tailored, nature-based health behavior interventions. This paper describes the protocol of the GoalRx Prescription Intervention (GPI) which was designed to leverage community resources to provide tailored park prescriptions for PHC patients. Methods: The GPI study was designed as a 3-arm, multi-site observational study. We enrolled low-income, rural adults either at-risk of or living with hypertension or diabetes (n = 75) from Federally Qualified Health Centers (FQHC) in two counties in North Carolina, USA into the 3-month intervention. Eligible participants self-selected to receive (1) a tailored park prescription intervention; (2) a tailored home/indoor PA prescription intervention; or (3) a healthy eating prescription (with no PA prescription beyond standard PA counseling advice that is already routinely provided in PHC) as the comparison group. The GPI app paired patient health data from the electronic health record with stated patient preferences and triggered app-integrated SMS motivation and compliance messaging directly to the patient. Patients were assessed at baseline and at a 3-month follow-up upon the completion of the intervention. The primary outcome (mean difference in weekly physical activity from baseline (T0) to post-intervention (T1) as measured by the Fitbit Flex 2) was assessed at 3 months. Secondary outcomes included assessment of the relationship between the intervention and biological markers of health, including body mass index (BMI), systolic and diastolic blood pressure, HbA1c or available glucose test (if applicable), and a depression screen score using the Patient Health Questionnaire 9. Secondary outcomes also included the total number of SMS messages sent, number of SMS messages responded to, number of SMS messages ignored, and opt-out rate. Discussion: The goal was to create a protocol utilizing eHealth technologies that addressed the specific needs of rural low-income communities and fit into the natural rhythms and processes of the selected FQHC clinics in North Carolina. This protocol offered a higher standard of health care by connecting patients to their PHC teams and increasing patient motivation to make longer-lasting health behavior changes.

Chronic Morphine-Induced Changes in Signaling at the A3 Adenosine Receptor Contribute to Morphine-Induced Hyperalgesia, Tolerance, and Withdrawal.

Treating chronic pain by using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance, and withdrawal, which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a twofold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord. Blocking ADK activity in the spinal cord provided greater than 90% attenuation of OIH and antinociceptive tolerance through A3 adenosine receptor (A3AR) signaling. Supplementing adenosine signaling with selective A3AR agonists blocked OIH and antinociceptive tolerance in rodents of both sexes. Engagement of A3AR in the spinal cord with an ADK inhibitor or A3AR agonist was associated with reduced dorsal horn of the spinal cord expression of the NOD-like receptor pyrin domain-containing 3 (60%-75%), cleaved caspase 1 (40%-60%), interleukin (IL)-1ß (76%-80%), and tumor necrosis factor (50%-60%). In contrast, the neuroinhibitory and anti-inflammatory cytokine IL-10 increased twofold. In mice, A3AR agonists prevented the development of tolerance in a model of neuropathic pain and reduced naloxone-dependent withdrawal behaviors by greater than 50%. These findings suggest A3AR-dependent adenosine signaling is compromised during sustained morphine to allow the development of morphine-induced adverse effects. These findings raise the intriguing possibility that A3AR agonists may be useful adjunct to opioids to manage their unwanted effects. SIGNIFICANCE STATEMENT: The development of hyperalgesia and antinociceptive tolerance during prolonged opioid use are noteworthy opioid-induced adverse effects that reduce opioid efficacy for treating chronic pain and increase the risk of dependence and abuse. We report that in rodents, these adverse effects are due to reduced adenosine signaling at the A3AR, resulting in NOD-like receptor pyrin domain-containing 3-interleukin-1ß neuroinflammation in spinal cord. These effects are attenuated by A3AR agonists, suggesting that A3AR may be a target for therapeutic intervention with selective A3AR agonist as opioid adjuncts.

Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain.

The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy.

Increasing placebo responses over time in U.S. clinical trials of neuropathic pain.

Recent failures of clinical trials of novel analgesics designed to treat neuropathic pain have led to much speculation about the underlying reasons. One often discussed possibility is that the placebo response in these trials has increased in recent years, leading to lower separation between the drug and placebo arms. Whether this has indeed occurred has not yet been adequately addressed. Here, we extracted data from published randomized controlled trials (RCTs) of drugs for the treatment of chronic neuropathic pain over the years 1990 to 2013. We find that placebo responses have increased considerably over this period, but drug responses have remained stable, leading to diminished treatment advantage. This trend has been driven by studies conducted in the United States. Consideration of participant and study characteristics revealed that in the United States but not elsewhere, RCTs have increased in study size and length. These changes are associated with larger placebo response. Analysis of individual RCT time courses showed different kinetics for the treatment vs placebo responses, with the former evolving more quickly than the latter and plateauing, such that maximum treatment advantage was achieved within 4 weeks.

Mitotoxicity in distal symmetrical sensory peripheral neuropathies.

Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor--that is, intraepidermal nerve fibres--of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.

Case report: Long-standing complex regional pain syndrome relieved by a cephalosporin antibiotic.

We describe a young woman who had had treatment-refractory complex regional pain syndrome (CRPS) for 6 years before receiving antibiotic treatment with cefadroxil (a cephalosporin derivative) for a minor infection. Cefadroxil reduced the patient's pain and motor dysfunction (dystonia and impaired voluntary movement) within days; the pain and motor disorder returned when cefadroxil was discontinued; and both again abated when cefadroxil was re-instituted. The patient has now had symptom relief for more than 3 years on continuing cefadroxil therapy. We discuss this case in the context of previous reports of antibiotic treatment relieving neuropathic pain in experimental animals.

Nerve resection, crush and re-location relieve complex regional pain syndrome type II: a case report.

This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower-limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves.

Increased expression of cutaneous α1-adrenoceptors after chronic constriction injury in rats.

UNLABELLED: α1-Adrenoceptor expression on nociceptors may play an important role in sympathetic-sensory coupling in certain neuropathic pain syndromes. The aim of this study was to determine whether α1-adrenoceptor expression was upregulated on surviving peptidergic, nonpeptidergic, and myelinated nerve fiber populations in the skin after chronic constriction injury of the sciatic nerve in rats. Seven days after surgery, α1-adrenoceptor expression was upregulated in the epidermis and on dermal nerve fibers in plantar skin ipsilateral to the injury but not around blood vessels. This α1-adrenoceptor upregulation in the plantar skin was observed on all nerve fiber populations examined. However, α1-adrenoceptor expression was unaltered in the dorsal hind paw skin after the injury. The increased expression of α1-adrenoceptors on cutaneous nociceptors in plantar skin after chronic constriction injury suggests that this may be a site of sensory-sympathetic coupling that increases sensitivity to adrenergic agonists after nerve injury. In addition, activation of upregulated α1-adrenoceptors in the epidermis might cause release of factors that stimulate nociceptive signaling. PERSPECTIVE: Our findings indicate that peripheral nerve injury provokes upregulation of α1-adrenoceptors on surviving nociceptive afferents and epidermal cells in the skin. This might contribute to sympathetically maintained pain in conditions such as complex regional pain syndrome, painful diabetic neuropathy, and postherpetic neuralgia.

Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase.

Many of the widely used anticancer drugs induce dose-limiting peripheral neuropathies that undermine their therapeutic efficacy. Animal models of chemotherapy-induced painful peripheral neuropathy (CIPN) evoked by a variety of drug classes, including taxanes, vinca alkaloids, platinum-complexes, and proteasome-inhibitors, suggest that the common underlying mechanism in the development of these neuropathies is mitotoxicity in primary nerve sensory axons (PNSAs) arising from reduced mitochondrial bioenergetics [eg adenosine triphosphate (ATP) production deficits due to compromised respiratory complex I and II activity]. The causative mechanisms of this mitotoxicity remain poorly defined. However, peroxynitrite, an important pro-nociceptive agent, has been linked to mitotoxicity in several disease states and may also drive the mitotoxicity associated with CIPN. Our findings reveal that the development of mechano-hypersensitivity induced by paclitaxel, oxaliplatin, and bortezomib was prevented by administration of the peroxynitrite decomposition catalyst Mn(III) 5,10,15,20-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) without interfering with their anti-tumor effects. Peak CIPN was associated with the nitration and inactivation of superoxide dismutase in the mitochondria, but not in the cytosol, as well as a significant decrease in ATP production within the PNSAs; all of these events were attenuated by MnTE-2-PyP(5+). Our results provide continued support for the role of mitotoxicity in the development of CIPN across chemotherapeutic drug classes, and identify peroxynitrite as a key mediator in these processes, thereby providing the rationale towards development of "peroxynitrite-targeted" therapeutics for CIPN.

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

UNLABELLED: Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. PERSPECTIVE: This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.

What is spontaneous pain and who has it?

UNLABELLED: Spontaneous pain is often discussed in the context of both chronic inflammatory and neuropathic pain conditions, and it has been suggested that spontaneous pain, rather than stimulus-evoked pain, may be the more significant clinical problem. The following issues are discussed here. First, it is suggested that the concept of spontaneous pain makes no sense when the pain is the result of an ongoing inflammatory reaction. Evidence is reviewed that indicates that spontaneous pain is present in patients with neuropathic pain, but perhaps only in a subset of such patients. Second, it is suggested that in the presence of allodynia and hyperalgesia, stimulation from the activities of daily life occurs very many times a day and that these stimulus-evoked pains may summate to give a fluctuating level of daily pain that both patients and investigators mistake for spontaneous pain. PERSPECTIVE: Which is more important-stimulus-evoked pain or spontaneous pain? This review suggests that to answer the question we will need to distinguish neuropathic spontaneous pain from inflammatory ongoing pain and to differentiate both from summated allodynic and hyperalgesic pains caused by the stimuli of daily life.

Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin.

The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.

Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy.

Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.

Repeated vulvovaginal fungal infections cause persistent pain in a mouse model of vulvodynia.

Provoked vestibulodynia, the most common form of vulvodynia (unexplained pain of the vulva), is a prevalent, idiopathic pain disorder associated with a history of recurrent candidiasis (yeast infections). It is characterized by vulvar allodynia (painful hypersensitivity to touch) and hyperinnervation. We tested whether repeated, localized exposure of the vulva to a common fungal pathogen can lead to the development of chronic pain. A subset of female mice subjected to recurrent Candida albicans infection developed mechanical allodynia localized to the vulva. The mice with allodynia also exhibited hyperinnervation with peptidergic nociceptor and sympathetic fibers (as indicated by increased protein gene product 9.5, calcitonin gene-related peptide, and vesicular monoamine transporter 2 immunoreactivity in the vaginal epithelium). Long-lasting behavioral allodynia in a subset of mice was also observed after a single, extended Candida infection, as well as after repeated vulvar (but not hind paw) inflammation induced with zymosan, a mixture of fungal antigens. The hypersensitivity and hyperinnervation were both present at least 3 weeks after the resolution of infection and inflammation. Our data show that infection can cause persistent pain long after its resolution and that recurrent yeast infection replicates important features of human provoked vulvodynia in the mouse.

Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel.

BACKGROUND: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. METHODS: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. RESULTS: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. CONCLUSIONS: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.

Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel.

The antineoplastic agent paclitaxel causes a dose-limiting distal, symmetrical, sensory peripheral neuropathy that is often accompanied by a neuropathic pain syndrome. In a low-dose model of paclitaxel-evoked painful peripheral neuropathy in the rat, we have shown that the drug causes degeneration of intraepidermal nerve fibers (IENFs), i.e. the fibers which give rise to the sensory afferent's terminal receptor arbor. However, we did not find any evidence for axonal degeneration in samples taken at the mid-nerve level. Here we aimed to determine whether the absence of degenerating peripheral nerve axons was due to sampling a level that was too proximal. We used electron microscopy to study the distal-most branches of the nerves innervating the hind paw glabrous skin of normal and paclitaxel-treated rats. We confirmed that we sampled at a time when IENF degeneration was prominent. Because degeneration might be easier to detect with higher paclitaxel doses, we examined a four-fold cumulative dose range (8-32 mg/kg). We found no evidence of degeneration in the superficial subepidermal axon bundles (sSAB) that are located just a few microns below the epidermal basal lamina. Specifically, for all three dose groups there was no change in the number of sSAB per millimeter of epidermal border, no change in the number of axons per sSAB and no change in the diameter of sSAB axons. We conclude that paclitaxel produces a novel type of lesion that is restricted to the afferent axon's terminal arbor; we name this lesion 'terminal arbor degeneration'.

Imaging studies in Freund's complete adjuvant model of regional polyarthritis, a model suitable for the study of pain mechanisms, in the rat.

OBJECTIVE: In view of the extensive distribution in the spinal cord of primary afferent nociceptive nerve fibers from the rat hind paw, a model of regional inflammation would be useful in the study of arthritis pain. However, the subcutaneous intraplantar injection of a single low dose of Freund's complete adjuvant (CFA) has been used mostly as an inflammation model. We undertook this study to characterize this model by means of conventional radiography, microfocal computed tomography, and bone densitometry and by examining changes in pain-related behavior. METHODS: Male rats were injected unilaterally with CFA or saline subcutaneously in the hind paw and killed 7, 15, and 30 days after injection. Pain-related behavior was studied using the Hargreaves, von Frey, and acetone tests. RESULTS: CFA-injected animals developed soft tissue inflammation and polyarthritis restricted to the joints of the injected hind paw. No signs of joint involvement were observed 7 days after CFA injection. On day 15 after CFA injection, there was widening of joint space indicative of joint effusion. By day 30 after CFA injection, there was evidence of joint damage with joint space narrowing, erosions, osteophyte formation, and joint deformity. There were no changes contralaterally or in saline-injected rats. Mechanical hyperalgesia and cold allodynia were present in the affected hind paw from day 1 through day 30. CONCLUSION: Signs of arthritis were strictly unilateral and started only 2 weeks after injection. Since the affected area has a broad representation in the spinal cord, this model has advantages over monarthritis models for the study of plastic changes in the dorsal horn of the spinal cord.