Peripherally acting kappa opioid receptor agonists (KORAs) belong to a novel class of opioid ligands which has a reduced ability to cross the blood–brain barrier and therefore acts without inducing central side effects.1
The aversive cognitive effects caused by activation of kappa opioid receptors in the CNS (dysphoria, hallucinations) have hindered the development of compounds acting by this mechanism. However, activation of kappa receptors located outside of the CNS (peripheral nerve endings and immune cells including T-cells, macrophage, mast cells, dorsal-root ganglion cells (DRG)) appears sufficient to modulate the transmission of pain and inflammatory signals. Activation of kappa opioid receptors with selective kappa opioid receptor agonists is also known to produce pharmacological effects that differ from activation of mu opioid receptors (e.g., no inhibition of GI transit, water retention, itch or induction of respiratory depression).2
Therefore, peripherally-restricted kappa agonists may represent a novel, better tolerated, class of anti-inflammatory and analgesic drugs for the treatment of acute and chronic pain.3
1Chalmers D. Peripheral kappa agonists. In: Raymond S. Sinatra et al. (eds.) The Essence of Analgesia and Analgesics. Cambridge University Press. pp. 490-491. 2010. 2Menzaghi F et al. Development of the novel, peripherally-selective kappa opioid agonist cr665 for the treatment of acute pain. Cara Therapeutics Inc. 3Menzaghi F et al. Development of the novel, peripherally-selective kappa opioid agonist cr665 for the treatment of acute pain. Cara Therapeutics Inc. 2008.