Neurophysiological assessment of joint nociceptors in the rat medial meniscus transection model of post-traumatic osteoarthritis.

OBJECTIVE: Meniscal injury is a common prelude to post-traumatic osteoarthritis (PTOA). Joint nerves can become damaged in arthritic joints leading to the manifestation of neuropathic pain. Both PTOA and neuropathic pain are more common in females; however, it is unknown whether the neural processing of joint pain is sex-specific. DESIGN: Male and female Wistar rats (230-286g) underwent unilateral medial meniscus transection (MMT) and allowed to recover for 28 days. Pain development was assessed over the time course by von Frey hair algesiometry and dynamic weight bearing. Recordings from joint primary afferents was carried out by electrophysiology at end-stage disease. Nerve damage and ß-endorphin levels were also compared between MMT and sham operated animals. RESULTS: Male MMT rats exhibited significant pain behaviour compared to sham control. Evoked afferent firing rate was heightened in male MMT animals. Female PTOA rats did not show signs of pain behaviour on each of the test days and the neurophysiological properties of their nociceptors was not different from control. Peripheral neuropathy was observed in about 30% of axons from male MMT animals compared to 15% in females. Systemic ß-endorphin levels in female PTOA rats was 91.0 ± 10.4 pg/mL and only 49.0 ± 5.0 pg/mL in males. CONCLUSIONS: Secondary allodynia and joint pain were observed in male but not female MMT rats. Joint nociceptors were sensitized in PTOA males but not in females. This lack of pain in females may be due to the absence of a peripheral neuropathy and greater endogenous opioid production.

Synovial nerve fiber density decreases with naturally-occurring osteoarthritis in horses.

OBJECTIVE: To measure the nerve fiber density in synovial membranes from healthy and OA equine joints and to investigate the relationship between synovial innervation and OA severity, synovial vascularity and synovitis. DESIGN: Twenty-five equine metacarpophalangeal joints were collected post-mortem. The joints were dissected and the macroscopic lesions of the articular cartilage were scored. Synovial membrane specimens (n = 50) were harvested, fixed, sectioned and scored histologically. Immunohistochemical staining and immunofluorescence with S-100 protein, that identifies nerve fibers, and ⍺-actin, that stains vascular smooth muscle, were also performed on site-matched specimens and the relationships between these tissues was interrogated. RESULTS: The nerve fiber density was higher in the superficial layer (≤200 µm) of the synovium when compared to the deeper layer in control equine joints (mean difference (95% C.I.): 0.054% (0.018%, 0.11%)). In osteoarthritic joints, synovial innervation decreased in the superficial layer with increasing macroscopic OA score (ß (SEM), 95% C.I.: -0.0061 (0.00021), -0.0011, -0.00017). The blood vessel density was also higher in the superficial layer of the synovium compared to the deep layer in the control (mean difference (95% C.I.): 1.1% (0.36%, 2.3%)) and OA (mean difference (95% C.I.): 0.60% (0.22%, 1.2%)) equine joints. Moreover, considering all synovial specimens, higher nerve fiber density in the deep layer positively correlated with blood vessel density (ß (SEM), 95% C.I.: 0.11 (0.036), 0.035, 0.18). CONCLUSION: The reduction in nerve fiber density with advanced cartilage degeneration suggests that peripheral neuropathy is associated with equine OA. Whether this link is associated with neuropathic pain, requires further investigation.

Estimating degradation-related settlement in two landfill-reclaimed soils by sand-salt analogues.

Landfill reclaimed soil here refers to largely degraded materials excavated from old landfill sites, which after processing can be reinstated as more competent fill, thereby restoring the former landfill space. The success of the process depends on the presence of remaining degradable particles and their influence on settlement. Tests on salt-sand mixtures, from which the salt is removed, have been used to quantify the impact of particle loss on settlement. Where the amount of particle loss is small, say 10% by mass or less, settlements are small and apparently independent of lost particle size. A conceptual model is presented to explain this behaviour in terms of nestling particles and strong force chains. At higher percentages of lost particles, greater rates of settlement together with some sensitivity to particle size were observed. The conceptual model was then applied to two landfill reclaimed soils, the long-term settlements of which were found to be consistent with the conceptual model suggesting that knowledge of particle content and relative size are sufficient to estimate the influence of degradable particles in landfill reclaimed soils.

Differences in the diagnosis and management of systemic lupus erythematosus by primary care and specialist providers in the American Indian/Alaska Native population.

Objectives The objective of this study is to investigate differences in the diagnosis and management of systemic lupus erythematosus (SLE) by primary care and specialist physicians in a population-based registry. Methods This study includes individuals from the 2009 Indian Health Service lupus registry population with a diagnosis of SLE documented by either a primary care provider or specialist. SLE classification criteria, laboratory testing, and medication use at any time during the course of disease were determined by medical record abstraction. Results Of the 320 individuals with a diagnosis of SLE, 249 had the diagnosis documented by a specialist, with 71 documented by primary care. Individuals with a specialist diagnosis of SLE were more likely to have medical record documentation of meeting criteria for SLE by all criteria sets (American College of Rheumatology, 79% vs 22%; Boston Weighted, 82% vs 32%; and Systemic Lupus International Collaborating Clinics, 83% vs 35%; p < 0.001 for all comparisons). In addition, specialist diagnosis was associated with documentation of ever having been tested for anti-double-stranded DNA antibody and complement 3 and complement 4 ( p < 0.001). Documentation of ever receiving hydroxychloroquine was also more common with specialist diagnosis (86% vs 64%, p < 0.001). Conclusions Within the population studied, specialist diagnosis of SLE was associated with a higher likelihood of having SLE classification criteria documented, being tested for biomarkers of disease, and ever receiving treatment with hydroxychloroquine. These data support efforts both to increase specialist access for patients with suspected SLE and to provide lupus education to primary care providers.

Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

It has been established that both adult and larval zebrafish are capable of showing nociceptive responses to noxious stimuli; however, the use of larvae to test novel analgesics has not been fully explored. Zebrafish larvae represent a low-cost, high-throughput alternative to traditional mammalian models for the assessment of product efficacy during the initial stages of drug development. In the current study, a novel model of nociception using zebrafish larvae is described. During the recovery from an acute exposure to low levels of acetic acid, larvae display innate changes in behaviour that may be indicative of nociception. To assess the usefulness of this model for testing potential analgesics, three known synthetic pain medications were assessed (ibuprofen, acetaminophen and tramadol) along with three naturally occurring products (honokiol, tetrahydrocannabinol and cannabidiol). When the effect of each compound on both the acetic acid recovery and control activity was compared there appeared to be both similarities and differences between the compounds. One of the most interesting effects was found for cannabidiol which appeared to oppose the activity change during the recovery period of AA exposed larvae while having a nominal effect on control activity. This would appear to be in line with current research that has demonstrated the nociceptive properties of cannabidiol. Here we have provided a novel model that will complement existing zebrafish models and will expand on the potential use of zebrafish larvae for studying both nociception and new analgesics.

Lysophosphatidic acid provides a missing link between osteoarthritis and joint neuropathic pain.

OBJECTIVE: Emerging evidence suggests that osteoarthritis (OA) has a neuropathic component; however, the identity of the molecules responsible for this peripheral neuropathy is unknown. The aim of this study was to determine the contribution of the bioactive lipid lysophosphatidic acid (LPA) to joint neuropathy and pain. DESIGN: Male Lewis rats received an intra-articular injection of 50 µg of LPA into the knee and allowed to recover for up to 21 days. Saphenous nerve myelination was assessed by g-ratio calculation from electron micrographs and afferent nerve damage visualised by activation transcription factor-3 (ATF-3) expression. Nerve conduction velocity was measured electrophysiologically and joint pain was determined by hindlimb incapacitance. The effect of the LPA antagonist Ki-16425 was also evaluated. Experiments were repeated in the sodium monoiodoacetate (MIA) model of OA. RESULTS: LPA caused joint nerve demyelination which resulted in a drop in nerve conduction velocity. Sensory neurones were ATF-3 positive and animals exhibited joint pain and knee joint damage. MIA-treated rats also showed signs of demyelination and joint neuropathy with concomitant pain. Nerve damage and pain could be ameliorated by Ki-16425 pre-treatment. CONCLUSION: Intra-articular injection of LPA caused knee joint neuropathy, joint damage and pain. Pharmacological blockade of LPA receptors inhibited joint nerve damage and hindlimb incapacitance. Thus, LPA is a candidate molecule for the development of OA nerve damage and the origin of joint neuropathic pain.

A commentary on modelling osteoarthritis pain in small animals.

OBJECTIVE: To describe the currently used animal models for the study of osteoarthritis (OA) pain, with an emphasis on small animals (predominantly mice and rats). OUTLINE: Narrative review summarizing the opportunities and limitations of the most commonly used small animal models for the study of pain and pain pathways associated with OA, and discussing currently used methods for pain assessment. Involvement of neural degeneration in OA is briefly discussed. A list of considerations when studying pain-related behaviours and pathways in animal models of OA is proposed. CONCLUSIONS: Animal models offer great potential to unravel the complex pathophysiology of OA pain, its molecular and temporal regulation. They constitute a critical pathway for developing and testing disease-specific symptom-modifying therapeutic interventions. However, a number of issues remain to be resolved in order to standardize pre-clinical OA pain research and to optimize translation to clinical trials and patient therapies.

The youth report version of the Child and Adolescent Scale of Participation (CASP): assessment of psychometric properties and comparison with parent report.

OBJECTIVE: The Child and Adolescent Scale of Participation (CASP) parent report is a brief and valid measure for use with children and youth with chronic conditions/disabilities that has been shown to have good coverage at the chapter level of the 'Activities and Participation' component of the International Classification of Functioning, Disability and Health. The purpose of this research was to assess the psychometric properties of a CASP youth self-report version, to further validate the parent report, and to compare parent and youth reports of youths' activity and participation. METHODS: Baseline data from a longitudinal study examining predictors of changes in quality of life for youth with chronic conditions/disabilities were used. CASP data were collected on 409 youth aged 11-17 with various conditions/disabilities using youth and parent reports. Internal consistency and factor structure were examined for both versions using Cronbach's alpha and exploratory factor analyses. Inter-rater agreement and magnitude of differences between youth and parent report were evaluated using intraclass correlation coefficients and paired t-tests respectively. Gender, age and condition/disability group differences in youth report CASP scores were examined using independent t-tests or analyses of variance. RESULTS: Strong internal consistency and internal structure validity was demonstrated for the CASP youth and parent report. The youth report factor structure was similar to the parent report in this and other studies. Youth reported their activity/participation to be significantly higher than did their parents. Significant differences in CASP scores were found among condition/disability groups. CONCLUSIONS: Findings show that, from a psychometric standpoint, the youth version of the CASP is a promising new self-report measure of activity and participation. As youth perceive their activity and participation levels differently than their parents, it is important to collect data from both sources to obtain a more comprehensive understanding of this aspect of youths' lives.

Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint.

BACKGROUND AND PURPOSE: The PAR(2) receptors are involved in chronic arthritis by mechanisms that are as yet unclear. Here, we examined PAR(2) activation in the rat knee joint. EXPERIMENTAL APPROACH: PAR(2) in rat knee joint dorsal root ganglia (DRG) cells at L3-L5, retrogradely labelled with Fluoro-gold (FG) were demonstrated immunohistochemically. Electrophysiological recordings from knee joint nerve fibres in urethane anaesthetized Wistar rats assessed the effects of stimulating joint PAR(2) with its activating peptide, 2-furoyl-LIGRLO-NH(2) (1-100 nmol·100 µL(-1) , via close intra-arterial injection). Fibre firing rate was recorded during joint rotations before and 15 min after administration of PAR(2) activating peptide or control peptide. Leukocyte kinetics in the synovial vasculature upon PAR(2) activation were followed by intravital microscopy for 60 min after perfusion of 2-furoyl-LIGRLO-NH(2) or control peptide. Roles for transient receptor potential vanilloid-1 (TRPV1) or neurokinin-1 (NK(1) ) receptors in the PAR(2) responses were assessed using the selective antagonists, SB366791 and RP67580 respectively. KEY RESULTS: PAR(2) were expressed in 59 ± 5% of FG-positive DRG cells; 100 nmol 2-furoyl-LIGRLO-NH(2) increased joint fibre firing rate during normal and noxious rotation, maximal at 3 min (normal; 110 ± 43%, noxious; 90 ± 31%). 2-Furoyl-LIGRLO-NH(2) also significantly increased leukocyte rolling and adhesion over 60 min. All these effects were blocked by pre-treatment with SB366791 and RP67580 (P < 0.05 compared with 2-furoyl-LIGRLO-NH(2) alone). CONCLUSIONS AND IMPLICATIONS: PAR(2) receptors play an acute inflammatory role in the knee joint via TRPV1- and NK(1) -dependent mechanisms involving both PAR(2) -mediated neuronal sensitization and leukocyte trafficking.

The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models.

Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We find EML4-ALK to be more sensitive to Hsp90 inhibition than either HER2 or mutant epidermal growth factor receptor (EGFR) with an inhibitory concentration (IC)(50) for protein degradation in the low nanomolar range. This degradation leads to a potent inhibition of downstream signaling pathways and to the induction of growth arrest and apoptosis in cells carrying the EML4-ALK fusion. To generate a causative link between the expression of EML4-ALK and sensitivity to IPI-504, we introduced an EML4-ALK cDNA into HEK293 cells and show that the expression of the fusion protein sensitizes cells to IPI-504 both in vitro and in vivo. In a xenograft model of a human NSCLC cell line containing the ALK rearrangement, we observe tumor regression at clinically relevant doses of IPI-504. Finally, cells that have been selected for resistance to ALK kinase inhibitors retain their sensitivity to IPI-504. We have recently observed partial responses to administration of IPI-504 as a single agent in a phase 2 clinical trial in patients with NSCLC, specifically in patients that carry an ALK rearrangement. This study provides a molecular explanation for these clinical observations.

Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain.

OBJECTIVE: The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA). METHOD: OA was induced in male Wistar rats by intra-articular injection of sodium monoiodo-acetate with a recovery period of 14 days. Immunohistochemistry was used to evaluate the expression of CB(2) and transient receptor potential vanilloid channel-1 (TRPV1) receptors in the dorsal root ganglion (DRG) and synovial membrane of sham- and sodium mono-iodoacetate (MIA)-treated animals. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint both before and following close intra-arterial injection of different doses of GW405833. The effect of intra-articular GW405833 on joint pain perception was determined by hindlimb incapacitance. An in vitro neuronal release assay was used to see if GW405833 caused release of an inflammatory neuropeptide (calcitonin gene-related peptide - CGRP). RESULTS: CB(2) and TRPV1 receptors were co-localized in DRG neurons and synoviocytes in both sham- and MIA-treated animals. Local application of the GW405833 significantly reduced joint afferent firing rate by up to 31% in control knees. In OA knee joints, however, GW405833 had a pronounced sensitising effect on joint mechanoreceptors. Co-administration of GW405833 with the CB(2) receptor antagonist AM630 or pre-administration of the TRPV1 ion channel antagonist SB366791 attenuated the sensitising effect of GW405833. In the pain studies, intra-articular injection of GW405833 into OA knees augmented hindlimb incapacitance, but had no effect on pain behaviour in saline-injected control joints. GW405833 evoked increased CGRP release via a TRPV1 channel-dependent mechanism. CONCLUSION: These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.

Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea pig model of spontaneous osteoarthritis.

Cathepsin K is a cysteine proteinase which is believed to contribute to osteoarthritis (OA) pathogenesis. This brief report evaluates the effect of the novel selective cathepsin K inhibitor AZ12606133 on cartilage metabolism in the Dunkin-Hartley guinea pig model of spontaneous OA. In parallel, electrophysiological studies were performed to determine whether acute and chronic treatment with the cathepsin K inhibitor could alter joint nociception. Acute treatment of OA knees with AZ12606133 had no effect on joint afferent nerve activity; however, prolonged (1 month) administration of the cathepsin K inhibitor delivered via a chronically implanted osmotic pump significantly reduced mechanosensitivity in response to both non-noxious and noxious joint movements. Urinal concentrations of the cartilage breakdown products cross-linked C-telopeptides of type II collagen (CTXII) were also reduced by chronic cathepsin K inhibition. These data suggest that prolonged AZ12606133 administration can reduce cartilage turnover and joint nociception in the Dunkin-Hartley guinea pig model of spontaneous OA.

Out-of-school time activity participation profiles of children with physical disabilities: a cluster analysis.

OBJECTIVE: To determine out-of-school activity participation profiles of school-aged children with physical disabilities. METHODS: Activity participation profiles were determined by cluster analysing 427 children's responses on multiple dimensions of participation (intensity, location, companionship, enjoyment, preference) in five activity types (recreational, active physical, social, skill-based, self-improvement). Socio-demographic, child, parent, family and environmental predictors of group membership were determined, along with child functioning, socio-demographic, self-concept and social support variables significantly associated with group membership. RESULTS: The cluster analysis revealed four groups, labelled Social Participators (a highly social and neighbourhood-focused group), Broad Participators (a group of high participators who enjoy participation), Low Participators (a group with low enjoyment and weak preferences) and Recreational Participators (a group of younger children who participate in recreational activities with family members). The groups showed meaningful differences across a range of socio-demographic, child, parent, family and environmental variables. CONCLUSIONS: The findings support an affective and contextual view of participation, indicating the importance of motivational theory and a person-environment approach in understanding the complexity of children's out-of-school activity participation.

Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception.

Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated through proteolytic cleavage. It is localized on epithelial, endothelial and inflammatory cells, as well as on transient receptor potential vanilloid 1 (TRPV1) receptor-expressing neurones. It plays an important role in inflammatory/nociceptive processes. Since there are few reports concerning PAR-2 function in joints, the effects of intraarticular PAR-2 activation on joint pain and inflammation were studied. Secondary hyperalgesia/allodynia, spontaneous weight distribution, swelling and inflammatory cytokine production were measured and the involvement of TRPV1 ion channels was investigated in rats and mice. Injection of the PAR-2 receptor agonist SLIGRL-NH(2) into the knee decreased touch sensitivity and weight bearing of the ipsilateral hindlimb in both species. Secondary mechanical allodynia/hyperalgesia and impaired weight distribution were significantly reduced by the TRPV1 antagonist SB366791 in rats and by the genetic deletion of this receptor in mice. PAR-2 activation did not cause significant joint swelling, but increased IL-1beta concentration which was not influenced by the lack of the TRPV1 channel. For comparison, intraplantar SLIGRL-NH(2) evoked similar primary mechanical hyperalgesia and impaired weight distribution in both WT and TRPV1 deficient mice, but oedema was smaller in the knockouts. The inactive peptide, LRGILS-NH(2), injected into either site did not induce any inflammatory or nociceptive changes. These data provide evidence for a significant role of TRPV1 receptors in secondary mechanical hyperalgesia/allodynia and spontaneous pain induced by PAR-2 receptor activation in the knee joint. Although intraplantar PAR-2 activation-induced oedema is also TRPV1 receptor-mediated, primary mechanical hyperalgesia, impaired weight distribution and IL-1beta production are independent of this channel.

Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation.

Proteinase activated receptors (PARs) are a newly identified family of G-protein-coupled receptors that are activated by proteinases released into tissues during inflammation. Evidence has accumulated which shows that PARs can exhibit both anti- and pro-inflammatory properties in different organ systems. During arthritis, proteinases are known to be released into the joint where they orchestrate tissue remodelling and degeneration. By activating PARs, these proteinases have the potential to modulate joint inflammation and pain by a highly targeted and selective receptor pathway. The recent identification of PARs on synovial fibroblasts, neutrophils, macrophages and mast cells is further evidence that this intriguing family of receptors could play a role in the pathogenesis and symptoms of arthritis. This review article provides an overview of the current knowledge regarding PARs and their emerging role in arthritis.

Central neural activation of hyperdynamic circulation in portal hypertensive rats depends on vagal afferent nerves.

BACKGROUND: Hyperdynamic circulation in portal hypertensive rats depends on central neural c-fos gene expression, but how the portal hypertensive signal activates central c-fos expression remains obscure. AIM: To elucidate the afferent pathway from the gut to the central cardiovascular regulatory nuclei in portal hypertensive rats. METHODS: Cervical vagus nerves and the coeliac ganglion were treated with topical capsaicin to denervate the sensory afferents. Surgical portal vein stenosis (PVS) was performed 3 weeks after denervation. Effectiveness of vagal afferent denervation was confirmed by absent oesophagus to brainstem transfer of the neural tracer cholera toxin-conjugated horseradish peroxidase. Fos, the protein product of the c-fos gene, was detected by immunohistochemistry in central cardiovascular regulatory nuclei. Vagal nerve activity was measured after acute portal hypertension induced by an inflatable cuff around the portal vein. Cardiac output and mean arterial pressure were recorded. RESULTS: In vagal capsaicin-treated rats, no horseradish peroxidase was detected in the brainstem after oesophageal injection. In vagal capsaicin-treated rats subjected to PVS, Fos expression was significantly decreased in both the solitary tract nucleus and paraventricular nucleus compared with untreated PVS rats. Acute portal hypertension stimulated vagal nerve electrical activity. The hyperdynamic circulation was completely abrogated in vagal capsaicin-treated PVS rats. Capsaicin induced no neural or haemodynamic changes in either sham-operated controls or coeliac ganglion-treated PVS rats. CONCLUSION: In portal hypertensive rats, central cardiovascular regulatory nuclei initiate hyperdynamic circulation in response to a gut signal associated with portal hypertension. Portal hypertension signals to the central nuclei via capsaicin-sensitive vagal afferent nerves.

In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints.

BACKGROUND AND PURPOSE: Cannabinoids (CBs) are known to be vasoactive and to regulate tissue inflammation. The present study examined the in vivo vasomotor effects of the CB2 receptor agonists JWH015 and JWH133 in rat knee joints. The effect of acute and chronic joint inflammation on CB2 receptor-mediated responses was also tested. EXPERIMENTAL APPROACH: Blood flow was assessed in rat knee joints by laser Doppler imaging both before and following topical administration of CB2 receptor agonists. Vasoactivity was measured in normal, acute kaolin/carrageenan inflamed and Freund's complete adjuvant chronically inflamed knees. KEY RESULTS: In normal animals, JWH015 and JWH133 caused a concentration-dependent increase in synovial blood flow which in the case of JWH133 was blocked by the selective CB2 receptor antagonist AM630 as well as the transient receptor potential vanilloid-1 (TRPV1) antagonist SB366791. The vasodilator effect of JWH133 was significantly attenuated in both acute and chronically inflamed knees. Given alone, AM630 had no effect on joint blood flow. CONCLUSION AND IMPLICATIONS: In normal joints, the cannabinomimetic JWH133 causes hyperaemia via a CB2 and TRPV1 receptor mechanism. During acute and chronic inflammation, however, this vasodilatatory response is significantly attenuated.

Electrophysiological evidence that the vasoactive intestinal peptide receptor antagonist VIP6-28 reduces nociception in an animal model of osteoarthritis.

OBJECTIVE: The present study examined whether local administration of the neuropeptide vasoactive intestinal polypeptide (VIP) could modulate joint nociception in normal rat knee joints and if the VIP antagonist VIP(6-28) could ameliorate joint mechanosensitivity in an animal model of osteoarthritis (OA). METHODS: OA was induced in male Wistar rats by intra-articular injection of 3mg sodium monoiodo-acetate with a recovery period of 14 days. Electrophysiological recordings were made from knee joint primary afferents in response to normal rotation and noxious hyper-rotation of the joint both before and following close intra-arterial injection of different doses of VIP and VIP(6-28). RESULTS: Local application of VIP to normal knees caused afferent firing rate to be significantly enhanced during normal rotation (up to 180% P<0.01; n=17) and during hyper-rotation (up to 37% P<0.01; n=17) of the knee. VIP-induced sensitization was blocked by pre-administration of the VIP receptor antagonist VIP(6-28). In the OA group, application of VIP(6-28) caused afferent firing rate to be significantly reduced during normal rotation (up to 45% P<0.05; n=17) and during hyper-rotation (up to 34% P<0.01; n=15) of the knee joint. CONCLUSION: These findings indicate that VIP is involved in peripheral sensitization of knee joint afferents especially in response to normal joint movements. OA-induced sensitization of knee joint afferents was inhibited by local administration of VIP(6-28), indicating that VIP is released into OA knee joints, potentially contributing to joint pain. As such, VIP(6-28) may prove to be a beneficial agent for the treatment of arthritis pain.