Abstract
Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6g) and thermal (40, 45 and 45°C) stimuli applied to the peripheral receptive field.MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1μg/50μl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60g) and noxious thermal-(45 and 48°C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain.
Highlights
Osteoarthritis (OA) is the most common form of joint disease, has a steadily rising prevalence due to an increasingly elderly and obese society, and represents one of the biggest contributors to the socioeconomic healthcare burden in the western world (Reginster, 2002)
Intra-articular injection of monosodium iodoacetate (MIA) produced a significant decrease in hind paw withdrawal threshold (PWT) to mechanical stimulation compared with the contralateral hind paw in MIA rats and sham control (Fig. 1a)
A significant reduction in weight bearing of the ipsilateral hind limb in MIA-injected rats was seen compared with the sham control group (Fig. 1b) indicative of enhanced discomfort evoked by weight on the limb in the MIA group
Summary
Osteoarthritis (OA) is the most common form of joint disease, has a steadily rising prevalence due to an increasingly elderly and obese society, and represents one of the biggest contributors to the socioeconomic healthcare burden in the western world (Reginster, 2002). Perhaps the most defining feature of clinical OA is chronic debilitating joint pain This can range from mild (dull aches) to severe (sharp stabbing pain) in the same patient, with consequent co-morbidities (mood and sleep problems) and decreased quality of life (Murphy et al, 2011). Without any pharmacological disease-modifying therapies currently in use, treatment is predominantly analgesic: paracetamol forms the current first line, followed by NSAIDs, opioids and steroids in line with disease progression and the severity of pain These medicines are inadequate for many OA patients due to limited analgesic efficacy and safety issues, especially with prolonged use. This significant unmet clinical burden necessitates a greater understanding of the mechanisms that initiate and maintain OA pain in order to develop alternative, more effective analgesics
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