Background/Purpose

Tropomyosin receptor kinase (Trk) receptors are a family of three closely related receptor tyrosine kinases; TrkA, TrkB and TrkC. Especially, the peripheral TrkA in sensory neuron is a promising target for musculoskeletal pain such as osteoarthritis (OA) since the activation of TrkA receptor by nerve growth factor (NGF) induces hyperalgesia and anti-NGF antibodies show potent analgesic effects in moderate to severe OA patients. However, sustained inhibition of TrkA in brain raises concerns about deteriorating cognitive impairment such as Alzheimer’s disease, because NGF/TrkA signal is important to maintain the function of cholinergic neuron. We discovered a highly selective and orally available Trk inhibitor which shows potent in vivo TrkA inhibitory activities at low plasma concentrations with a low brain penetration. In this study, we evaluated the analgesic effects of peripheral-specific Trk inhibitor on monosodium iodoacetate (MIA)-induced OA pain in rats.

Methods

Male SD rats (215~265 g) were briefly anaesthetized with isoflurane, and 3 mg MIA solution or saline was intra-articularly injected into right knee. The peripheral-specific Trk inhibitor or vehicle (distilled water containing 20% Wellsolve) was orally administrated twice a day for 8 days from 14 day after MIA injection. Morphine was subcutaneously administrated 1 hour before evaluation of pain-related behavior. Pain-related behavior was evaluated by the percent weight borne on right leg.

Results

The peripheral-specific Trk inhibitor does-dependently inhibited the pain-related behavior of MIA-treated rats in which acetaminophen and nonsteroidal anti-inflammatory drugs did not show analgesic effects. The analgesic effect of it at 1 mg/kg b.i.d. or more was comparable to that of morphine at 3 mg/kg which significantly impaired motor coordination in rats. Although repeated administration of high doses of peripheral-specific Trk inhibitor for 14 days increased food consumption and weight gain in normal rats, there was at least 36-fold margin calculated by area under the concentration-time curve between effective dose in MIA model and no affecting dose to them.

Conclusion

The selective and peripheral-specific Trk inhibitor will be a potent and safer medication for OA pain.

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« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-and-peripheral-specific-trk-inhibitor-shows-potent-analgesic-effect-comparable-to-morphine-in-rat-osteoarthritis-model-without-cns-toxicity/