Peripherally restricted kappa opioid agonists have been developed to target kappa opioid receptors located on visceral and somatic afferent nerves for relief of inflammatory, visceral, and neuropathic chronic pain. The recently shown efficacy of these analgesics combined with a possible lower abuse potential and side effect burden than mu opioid receptor agonists makes delta and peripherally restricted kappa opioid receptor agonists promising targets for treating pain.1
The kappa opioid system consists of the dynorphin (Dyn) family of neuropeptides and KORs. Evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is free from the abuse potential. It has been well established that the Dyn/KOR system exerts an inhibitory effect on brain reward function by suppressing dopamine release from the mesolimbic reward pathway and the nigrostriatal pathway. These brain regions are intimately associated with the development of drug dependence. Numerous studies in both nonhuman primates and rats have demonstrated that kappa agonists functionally attenuate many behavioral effects of cocaine, including behavioral sensitization place preference, and self-administration. Administration of kappa agonists also attenuates the reinstatement of extinguished drugtaking behavior in an animal model of relapse. These inhibitory effects of kappa agonists on cocaineinduced abuse-related behaviors are possibly achieved by inhibiting the release of DA from dopaminergic neurons.2
Analgesics such as morphine cause many side effects including addiction, but kappa-opioid receptor agonists can produce antinociception without morphine-like side effects. In one study, the kappa-opioid receptor agonist LPK-26 showed a high affinity to kappa-opioid receptor with the Ki value of 0.64 nM and the low affinities to micro-opioid receptor and delta-opioid receptor with the Ki values of 1170 nM and >10,000 nM, respectively. In vivo, LPK-26 was more potent than (-)U50,488H and morphine in analgesia, with the ED50 values of 0.049 mg/kg and 0.0084 mg/kg. Taken together, results show that LPK-26 is a novel selective kappa-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence.3
Kappa opioid receptor agonists that act within the CNS are reported to produce dysphoria and hallucinations. These symptoms have not been reported with single or multiple intravenous doses of the kappa-opioid receptor agonist CR845.4 CR845’s D-amino acid–based peptidic structure confers limited membrane permeability by diffusion or active transport mechanisms and results in CR845 having limited access to the central nervous system (CNS).
In a single-center, randomized, double-blind, active- and placebo-controlled, 4-way crossover study, overall Drug Liking and Take Drug Again VAS scores were significantly lower in either dose of CR845 (P<0.0001) vs. a Schedule IV drug pentazocine (0.5 mg/kg). Overall Drug Liking and Take Drug Again VAS scores following either dose of CR845 were similar to those observed with placebo.5
