Jason J. McDougall

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.

Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis

IntroductionA subgroup of voltage gated sodium channels including Nav1.8 are exclusively expressed on small diameter primary afferent neurons and are therefore believed to be integral to the neurotransmission of nociceptive pain. The present study examined whether local application of A-803467, a selective blocker of the Nav 1.8 sodium channel, can reduce nociceptive transmission from the joint in a rodent model of osteoarthritis (OA).MethodsOA-like changes were induced in male Wistar rats by an intra-articular injection of 3 mg sodium monoiodoacetate (MIA). Joint nociception was measured at day 14 by recording electrophysiologically from knee joint primary afferents in response to non-noxious and noxious rotation of the joint both before and following close intra-arterial injection of A-803467. The effect of Nav1.8 blockade on joint pain perception and secondary allodynia were determined in MIA treated animals by hindlimb incapacitance and von Frey hair algesiometry respectively.ResultsA-803467 significantly reduced the firing rate of joint afferents during noxious rotation of the joint but had no effect during non-noxious rotation. In the pain studies, peripheral injection of A-803467 into OA knees attenuated hindlimb incapacitance and secondary allodynia.ConclusionsThese studies show for the first time that the Nav1.8 sodium channel is part of the molecular machinery involved in mechanotransduction of joint pain. Targeting the Nav1.8 sodium channel on joint nociceptors could therefore be useful for the treatment of OA pain, avoiding the unwanted side effects of non-selective nerve blocks.

Murine autoimmune arthritis is exaggerated by infection with the rat tapeworm, Hymenolepis diminuta.

Infection with helminth parasites triggers strong and stereotypic immune responses in humans and mice, which can protect against specific experimentally-induced autoimmune diseases. We have shown that infection with the rat tapeworm, Hymenolepis diminuta, confers a protective effect on FCA-induced joint inflammation. Here, we investigated the effect of a prophylactic infection with H. diminuta on the K/BxN-serum model of polyarthritis in BALB/c mice. Mice were infected with 10 cysticercoids of H. diminuta by oral gavage and 8 days later arthritis was induced by i.p. injection of K/BxN arthritogenic serum. Joint swelling and pain measurements were recorded throughout a 13 day time course. At necropsy, joints and blood serum were collected. K/BxN-treated mice developed joint inflammation in the front paws, hind paws and knees as shown by increased swelling, mechanical allodynia and myeloperoxidase activity. Mice infected with H. diminuta had more severe disease, with increased eosinophil peroxidase activity in their paws and greater inflammatory infiltrate and synovitis in the knee joints. Hymenolepis diminuta-infected mice displayed significant increases in serum levels of C5a and mast cell protease-1 compared with K/BxN-serum only treatment, the latter being indicative of mast cell activation. In contrast to the protective effect of infection with H. diminuta in FCA-induced monoarthritis, infection with this helminth exacerbated K/BxN serum-induced polyarthritis in BALB/c mice. This correlated with increases in C5a and mast cell activation: factors critical in the development of K/BxN-induced arthritis. Thus, while data accumulate from animal models showing that infection with helminth parasites may be beneficial for a variety of auto-inflammatory diseases, our findings demonstrate the potential for helminths to exacerbate disease. Hence care is needed when helminth therapy is translated into a clinical setting.

Activation of PAR2 receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint

The PAR2 receptors are involved in chronic arthritis by mechanisms that are as yet unclear. Here, we examined PAR2 activation in the rat knee joint.

Mechanisms and Mediators That Drive Arthritis Pain

There are over 100 different types of arthritis and each can differ greatly in their aetiology and pathophysiology; however, one characteristic that is common to all arthritic conditions is joint pain. Musculoskeletal pain is the leading cause of disability in the world, and the number one reason arthritis patients visit their primary care physician. Despite the prevalence and burden of arthritis pain, current analgesics lack sufficient efficacy and are plagued by multiple adverse side effects. In this review, we outline the current landscape of research concerning joint pain, drawing from both preclinical and clinical studies. Specifically, this review is a discussion of the different neurophysiological processes that occur during joint disease and how inflammatory and neuropathic aspects contribute to the development of arthritis pain.

Tapping into the endocannabinoid system to ameliorate acute inflammatory flares and associated pain in mouse knee joints

IntroductionDuring the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common. Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation. One enzyme responsible for endocannabinoid breakdown is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis.MethodsAcute joint inflammation was induced in male C57BL/6 mice by intra-articular injection of 2% kaolin/2% carrageenan. After 24 hr, articular leukocyte kinetics and blood flow were used as measures of inflammation, while hindlimb weight bearing and von Frey hair algesiometry were used as measures of joint pain. The effects of local URB597 administration were then determined in the presence or absence of either the cannabinoid (CB)1 receptor antagonist AM251, or the CB2 receptor antagonist AM630.ResultsURB597 decreased leukocyte rolling and adhesion, as well as inflammation-induced hyperaemia. However, these effects were only apparent at low doses and the effects of URB597 were absent at higher doses. In addition to the anti-inflammatory effects of URB597, fatty acid amide hydrolase (FAAH) inhibition improved both hindlimb weight bearing and von Frey hair withdrawal thresholds. The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both CB1 and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation. The analgesic effects of URB597 were CB1 mediated.ConclusionsThese results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.

Neutrophil elastase induces inflammation and pain in mouse knee joints via activation of proteinase-activated receptor-2.

Neutrophil elastase plays a crucial role in arthritis. Here, its potential in triggering joint inflammation and pain was assessed, and whether these effects were mediated by proteinase‐activated receptor‐2 (PAR2).

The role of kinin B1 receptor and the effect of angiotensin I-converting enzyme inhibition on acute gout attacks in rodents

Objective Verify the role of the kinin B1 receptors (B1R) and the effect of ACE inhibitors (ACEi) on acute gout induced by monosodium urate (MSU) crystals in rodents. Methods Painful (overt pain and allodynia) and inflammatory parameters (joint oedema, leukocyte trafficking, interleukin-1β levels) of acute gout attacks were assessed several hours after an intra-articular injection of MSU (1.25 or 0.5 mg/articulation) into the ankle of rats or mice, respectively. The role of B1R was investigated using pharmacological antagonism or gene deletion. Additionally, B1R immunoreactivity in ankle tissue and sensory neurons, kininase I activity and des-Arg9-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on a low dose of MSU (0.0125 mg/articulation)-induced inflammation. Results Kinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased B1R expression in articular tissues, the content of the B1 agonist des-Arg9-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. A low dose of MSU crystals, which did not induce inflammation in control animals, caused signs of acute gout attacks in ACEi-treated animals that were B1R-dependent. Conclusions Kinin B1R contributes to acute gouty attacks, including the ones facilitated by ACEi. Therefore, B1R is a potential therapeutic target for the treatment and prophylaxis of gout, especially in patients taking ACEi.

Preclinical Assessment of Inflammatory Pain

While acute inflammation is a natural physiological response to tissue injury or infection, chronic inflammation is maladaptive and engenders a considerable amount of adverse pain. The chemical mediators responsible for tissue inflammation act on nociceptive nerve endings to lower neuronal excitation threshold and sensitize afferent firing rate leading to the development of allodynia and hyperalgesia, respectively. Animal models have aided in our understanding of the pathophysiological mechanisms responsible for the generation of chronic inflammatory pain and allowed us to identify and validate numerous analgesic drug candidates. Here we review some of the commonly used models of skin, joint, and gut inflammatory pain along with their relative benefits and limitations. In addition, we describe and discuss several behavioral and electrophysiological approaches used to assess the inflammatory pain in these preclinical models. Despite significant advances having been made in this area, a gap still exists between fundamental research and the implementation of these findings into a clinical setting. As such we need to characterize inherent pathophysiological pathways and develop new endpoints in these animal models to improve their predictive value of human inflammatory diseases in order to design safer and more effective analgesics.

Clinical Implications for Cannabinoid Use in the Rheumatic Diseases Potential for Help or Harm

Cannabinoids as therapeutic agents in traditional medicine are both lauded and maligned. The ubiquitous use in years gone by once made cannabinoids a mainstay of the physician’s dispensary, yet the understanding of the pharmacology of these drugs is relatively recent. The physiologic and psychoactive effects of the cannabis, or hemp, plant, cultivated in ancient times for the production of textiles, led to ceremonial, therapeutic, and eventual recreational use, beginning in the Himalayan region of central Asia and with the first recorded medicinal use in China in 2700 BC (1). In the Western world, 2 paths of scientific study of cannabinoids have been followed. In the earliest studies, 19th century French psychiatrists focused on the effects on mood, whereas British physicians explored the sedative, analgesic, hypnotic, and anticonvulsive properties (1). In the early 20th century, interest in cannabis as a therapeutic agent waned following the introduction of drugs with a more reliable therapeutic profile, such as opiates. With increasing global concerns about narcotic addiction, cannabis was misclassified as a narcotic, similar to heroin, opium, and cocaine, at the Geneva International Convention on Narcotics Control in 1925, which resulted in a ban on cannabis for recreational use in the UK in 1928 and criminalization in the US in 1937 (1,2). Renewed interest in the therapeutic effects of cannabinoids emerged following the identification and cloning of cannabinoid receptors in the late 1980s and 1990 (3–5). The endocannabinoid system, found throughout the animal kingdom, comprises endogenous ligands, termed endocannabinoids, and receptors. This system has effects on pain mechanisms, immune function, inflammation, and bone health, as has been noted in the laboratory setting. However, formal clinical study has been limited. Therefore, the true efficacy and risk/ benefit ratio with regard to the therapeutic effects of cannabinoids, whether derived from the hemp plant Cannabis sativa or synthesized from cannabis derivatives, remain controversial (6). The use of cannabinoids as therapeutic agents has mostly remained outside mainstream medicine in modern times and is further prejudiced by the recreational use of marijuana, a drug associated with abuse with a reported usage rate of 4% of the global population (2,3). Because more than 60 alkaloids are present in the plant form, and because there has been increasing identification of endocannabiMary-Ann Fitzcharles, MB, ChB, FRCPC: McGill University Health Center and McGill University, Montreal, Quebec, Canada; Jason McDougall, PhD: Dalhousie University, Halifax, Nova Scotia, Canada; Peter A. Ste-Marie, BA: McGill University Health Center and University of Montreal, Montreal, Quebec, Canada; Ivan Padjen, MD: University Hospital Centre Zagreb and University of Zagreb, Zagreb, Croatia. Dr. Fitzcharles has received consulting fees, speaking fees, and/or honoraria from Eli Lilly, Janssen, Pfizer, and Purdue Pharma (less than