RESUMO
Osteoarthritis (OA) pain originates in the joint by sensitization of articular nociceptors. While behavioural assessments provide valuable information regarding pain symptoms, the techniques are subjective and open to interpretation by the experimenter. This study used in vivo electrophysiological approaches to measure objectively joint nociceptor properties in three rodent models of OA. Single unit extracellular recordings of joint mechanosensitive afferents were carried out in male and female rats following either (1) transection of the medial meniscus (MMT: post-traumatic OA), (2) intra-articular injection of sodium monoiodoacetate (MIA: chemically-induced OA), or (3) intra-articular injection of lysophosphatidic acid (LPA: neuropathic OA). In naïve male control rats, the mechanical threshold of joint mechanonociceptors (23.5⯱â¯1.8 mNm) was significantly reduced with MMT (9.4⯱â¯1.1 mNm) and MIA (15.1⯱â¯1.6 mNm). In females, the mechanical threshold of naïve rats (23.2⯱â¯3.1 mNm) was reduced following induction of MMT (8.3⯱â¯1.0 mNm) and LPA (10.6⯱â¯2.2 mNm). Afferent firing frequency increased in male MMT (â¼275â¯%), LPA (â¼175â¯%), MIA (225â¯%), and female MMT (â¼146â¯%), LPA (â¼200â¯%), and MIA (â¼192â¯%). Mechanical threshold and evoked firing were negatively correlated in all models for both sexes except LPA rats (maleâ¯+â¯female) and female MMT. These data indicate that MMT, MIA, and LPA induce peripheral sensitization of joint afferents thereby validating their use in OA pain studies.
RESUMO
Neuronal electrochemical signals involve the flux of sodium ions through voltage-gated sodium channels (NaV) located in the neurolemma. Of the nine sodium channel subtypes, NaV-1.7, 1.8, and 1.9 are predominantly located on nociceptors, making them prime targets to control pain. This review highlights some of the latest discoveries targeting NaV channel activity, including: (1) charged local anaesthetic derivatives; (2) NaV channel toxins and associated small peptide blockers; (3) regulation of NaV channel accessory proteins; and (4) genetic manipulation of NaV channel function. While the translation of preclinical findings to a viable treatment in humans has remained a challenge, a greater understanding of NaV channel physiology could lead to the development of a new stream of therapies aimed at alleviating chronic pain.
Assuntos
Dor , Canais de Sódio Disparados por Voltagem , Humanos , Dor/tratamento farmacológico , Dor/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
Increased afferent input resulting from painful injury augments the activity of central nociceptive circuits via both neuron-neuron and neuron-glia interactions. Microglia, resident immune cells of the central nervous system (CNS), play a crucial role in the pathogenesis of chronic pain. This study provides a framework for understanding how peripheral joint injury signals the CNS to engage spinal microglial responses. During the first week of monosodium iodoacetate (MIA)-induced knee joint injury in male rats, inflammatory and neuropathic pain were characterized by increased firing of peripheral joint afferents. This increased peripheral afferent activity was accompanied by increased Iba1 immunoreactivity within the spinal dorsal horn indicating microglial activation. Pharmacological silencing of C and A afferents with co-injections of QX-314 and bupivacaine, capsaicin, or flagellin prevented the development of mechanical allodynia and spinal microglial activity after MIA injection. Elevated levels of ATP in the cerebrospinal fluid (CSF) and increased expression of the ATP transporter vesicular nucleotide transporter (VNUT) in the ipsilateral spinal dorsal horn were also observed after MIA injections. Selective silencing of primary joint afferents subsequently inhibited ATP release into the CSF. Furthermore, increased spinal microglial reactivity, and alleviation of MIA-induced arthralgia with co-administration of QX-314 with bupivacaine were recapitulated in female rats. Our results demonstrate that early peripheral joint injury activates joint nociceptors, which triggers a central spinal microglial response. Elevation of ATP in the CSF, and spinal expression of VNUT suggest ATP signaling may modulate communication between sensory neurons and spinal microglia at 2 weeks of joint degeneration.
Assuntos
Artrite Experimental/fisiopatologia , Microglia/fisiologia , Neurônios Aferentes/fisiologia , Medula Espinal/fisiopatologia , Trifosfato de Adenosina/fisiologia , Animais , Artralgia/terapia , Modelos Animais de Doenças , Feminino , Hiperalgesia/fisiopatologia , Ácido Iodoacético/farmacologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Serine proteases are elevated in arthritic joints where they can cleave protease activated receptors (PARs) to modulate pain and inflammation. Activation of protease-activated receptor 4 (PAR4) has been implicated in inflammatory joint pain. Whether PAR4 is involved in osteoarthritis (OA) pain has not yet been explored. The aim of this study was to compare the role of PAR4 in modulating early versus late stage OA pain using two models of OA viz. monoiodoacetate (MIA) and medial meniscal transection (MMT). G-ratio calculation and electron microscopy analysis revealed saphenous nerve demyelination and structural damage during late stage but not early OA in both models. Using immunohistochemistry, neuronal expression of PAR4 was higher in early versus late OA. Systemic administration of the PAR4 antagonist pepducin P4pal10 reduced both secondary allodynia (von Frey hair algesiometry) and joint nociceptor firing (single unit recordings) in MMT and MIA animals compared to vehicle-treated animals in early OA. The PAR4 antagonist was ineffective at altering pain or joint afferent firing in post-inflammatory OA. During the acute phase of the models, joint inflammation as determined by laser speckle contrast analysis and intravital microscopy could be partially blocked by pepducin P4pal10. Compared to late-stage disease, inflammatory cytokines were elevated in early MIA and MMT rats. These findings suggest that PAR4 may be a viable target to treat the pain of early onset OA or during episodic inflammatory flares.
RESUMO
Osteoarthritis (OA) is a degenerative joint disease that increases in prevalence with advanced age. While a multitude of factors contribute to the development of OA, ageing has been implicated as a major driving force leading to an inability of the joint to repair itself and maintain normal health. In aged individuals, changes in joint cellular composition and signalling mechanisms have been observed which could lead to the development of degenerative joint disease. Senescent cells found in both aged and OA joints release senescent-associated mediators which can destroy articular tissues. These changes in addition to the chronic pro-inflammatory environment associated with ageing may hinder the ability of the joint to repair culminating in OA. We hypothesise that frailty may also drive OA development by creating an inflammatory environment that can interfere with normal tissue health. The molecular and biochemical changes associated with OA may in turn promote frailty resulting in an exorable deterioration of the joint. Frailty may therefore be considered an additional risk factor for the development of OA.
Assuntos
Envelhecimento/metabolismo , Condrócitos/metabolismo , Fragilidade/metabolismo , Osteoartrite/metabolismo , Transdução de Sinais , Envelhecimento/patologia , Senescência Celular , Condrócitos/patologia , Fragilidade/patologia , Fragilidade/fisiopatologia , Humanos , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Fatores de RiscoRESUMO
Joint neuropathic pain occurs in a subset of arthritis patients, and lysophosphatidic acid (LPA) has been implicated as a mediator of joint neuropathy. The mechanism by which LPA promotes neuropathic pain is unknown but may be related to altered signalling of the voltage-gated sodium channel Nav1.8 located on nociceptors. Because arthritis and neuropathic pain are more prevalent in females, this study aimed to explore potential sex differences in the development of LPA-induced joint neuropathy and whether Nav1.8 played a role in the associated neuropathic pain. Joint neuropathy was induced in male and female Wistar rats (179-284 g) by intra-articular injection of 50-µg LPA. Pain behaviour was assessed over 21 days using von Frey hair algesiometry. On day 21, electrophysiological recordings of joint primary afferents were conducted to measure peripheral sensitisation. Saphenous nerve morphology and expression of the nerve-damage marker ATF3 and Nav1.8 in ipsilateral dorsal root ganglions were compared on the basis of sex. The analgesic properties of the selective Nav1.8 antagonist A-803467 was determined in pain behaviour and electrophysiology experiments. Females developed more severe mechanical allodynia than males after LPA treatment. Lysophosphatidic acid caused more pronounced demyelination of the saphenous nerve in females, but no sex differences were observed in the expression of ATF3 or Nav1.8 in dorsal root ganglion neurones. Blockade of Nav1.8 channels with A-803467 resulted in a decrease in joint mechanosensitivity and secondary allodynia with females exhibiting a greater response. These findings suggest that LPA has sex-specific effects on joint neuropathy and Nav1.8 gating, which should be considered when treating neuropathic arthritis patients.