NaViGating arthritis pain

Joints are complex organs with specialized tissues, sophisticated biomechanics, and an intricate neural network. The ligaments, menisci, cartilage, and bony contours of a joint must be well maintained to permit fluid, almost frictionless movement. Within the lower extremities, joints are subjected to high loads which predispose them to a significant risk of trauma both at the microscopic and macroscopic level. Unfortunately, joints are poor at launching an effective healing response to any damage and over time the organ typically fails. Such is the case with osteoarthritis (OA), the most prevalent joint disease currently estimated to affect almost 600 million people worldwide.5 In the absence of any compelling treatment to abate disease progression or reverse structural degeneration, pain alleviation is still the mainstay of OA management. Over the years, a number of scientific advances have been made in our understanding of the mechanisms responsible for OA pain, and one of the most promising targets are voltage-gated sodium channels (NaV) located on peripheral nociceptors.9 The origin of arthritis pain occurs in the joint itself by the activation and sensitization of afferent nerve terminals that ramify throughout the synovium, subchondral bone, the outer third of the menisci, and articular ligaments. The generation and propagation of electrical impulses in these nociceptive nerves is orchestrated by voltage-gated sodium channels, particularly NaV1.7, 1.8, and 1.9. Nonselective blockade of all NaV channels, with for example, lidocaine, is not practical for long-term pain control because other neural functions (eg, vasoregulation, proprioception, touch) would also be affected. Targeting NaV1.7 to 1.9 on joint nociceptors would circumvent these limitations allowing for selective blockade of pain neurotransmission. The first report testing this targeted approach in OA found that blocking the NaV1.8 channel with the small molecule A-803467 reduced joint afferent hypersensitivity and pain in a rodent model.15 This observation was corroborated by Rahman and Dickenson13 who in addition found that NaV1.7 blockade with the tarantula venom toxin ProTxII reduced central sensitization and OA pain. The disadvantages of small molecule blockers and toxins for the treatment of chronic pain include modest channel selectivity, limited channel occupancy, and short duration of effect. Many strategies have been used to circumvent some of these drawbacks including (1) the use of charged local anaesthetics combined with nociceptor-specific large cation channel constructs to improve tissue specificity and prolong efficacy17,18; (2) genetic interference of nociceptor NaV channel production using CRISPR-Cas9 technology to downregulate cell-surface receptor expression and signaling10; and (3) targeting accessory proteins associated with NaVs to alter ion channel trafficking and gating.16,19 In the current issue of PAIN, Hestahave et al.6 build on their previous work to develop a strategy that alters NaV1.7 trafficking to modulate pain in a preclinical model of OA. The collapsin response mediator protein-2 (CRMP2) is a cytosolic phosphoprotein involved in neural development and has been associated with various neurodegenerative diseases.2 Phosphorylation or attachment of a small ubiquitin-related modifier (SUMO) can increase the functionality of CRMP2 leading to increased trafficking of NaV1.7 to the neurolemma and pain chronification.3,11 The Khanna team have recently developed a small molecule called 194 which can disrupt SUMOylation of NaV1.7 leading to reduced surface expression of the channel and hence reduced pain in multiple preclinical models.1,7 Here, the authors found in the monoiodoacetate (MIA) model of OA that intraperitoneal administration of 194 dose-dependently reduced thermal and mechanical allodynia, further validating the analgesic potential of this molecule. Pain and aversive behaviours were only tested 2 hours after NaV1.7 channel inhibition showing a clear acute effect of 194; however, the long-term effect of this molecule in OA was not assessed here and therefore requires further development for sustained pain relief. Indeed, one of the main limitations of cation channel small molecule blockers and natural venoms/toxins is that they have a relatively small therapeutic window which restricts their utility for the treatment of chronic pain conditions.4 A number of innovative approaches have been undertaken to prolong the duration of NaV channel-mediated analgesia including combination therapies with other analgesics,8 use of charged local anaesthetics to promote intracellular access to cytosolic subunits,18 highly selective blocking antibodies with slow dissociation properties,14 and gene therapy techniques to silence channel activity and gating.10 Also shown here was that the analgesic effect of 194 in OA was equally efficacious in males and females which contrasts with NaV1.8 channel blockade which is more effective in females only12 highlighting a potential sex difference between the NaV channels in disease situations. To determine where along the pain pathway 194 could be targeting NaV1.7 channels, Hestahave et al. carried out a variety of tests to investigate the effect of the molecule in the dorsal root ganglia, spinal cord, and brainstem. In the periphery, incubation of acutely dissociated dorsal root ganglia neurons from MIA animals with 194 reduced peak sodium current density by about 50%. The authors have previously found that 194 can reduce dorsal horn neuronal hyperexcitability,1 although direct electrophysiological evidence of central inhibition in the MIA model was not shown here. Nevertheless, chemically evoked release of calcitonin gene-related peptide in lumbar spinal cord samples was significantly reduced by 194 in this preclinical model of OA. Finally, calcium imaging of glutamatergic neurons in the parabrachial nucleus revealed that 194 could normalize the heightened MIA-induced activity in this brain region. Taken together, these data indicate that in OA 194 was able to reduce neuronal sensitization at all levels of the pain pathway. In summary, Hestahave et al. have convincingly shown that disruption of NaV1.7 trafficking by inhibiting CRMP2 SUMOylation has the potential to reduce OA pain thereby opening a novel therapeutic channel as we NaVigate the treatment of OA pain. Conflict of interest statement The author has no conflicts of interest to declare.

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