The Journal of Pain | 2019
(256) Peripherally-Restricted Dual-Acting Kappa/Delta Opioid Agonist (CA1001) Prevents Formalin-Induced Hyperalgesia
Abstract
Peripheral\xa0mu-opioid receptors (MOR) are responsible for opioid-induced constipation, but in the uninjured state do not participate significantly in the pain pathway. On the other hand,\xa0kappa-\xa0(KOR) and\xa0delta-opioid (DOR) receptors are constitutively present in the periphery. However, the DOR only becomes active following the induction of the inflammatory response. The relative contribution of DOR agonism to KOR agonism was examined in the formalin model. Subcutaneous plantar injection of formalin causes a bi-phasic nocifensive behavioral response in rodents. The early phase (phase 1) lasts for about 5-10 minutes, following which an interphase occurs without any discernible nociceptive reactions, after which the late phase (phase 2) nociceptive reaction ensues continuing from about 20-60 minutes. Phase 2 of the formalin model is a model of continuously present persistent pain. The late phase (phase 2), in particular, is considered as a pharmacodynamic surrogate of central sensitization. A novel dual-acting, peripherally-restricted kappa-delta opioid agonist (CA1001) was compared to a peripherally-restricted kappa agonist (ICI204448) in the formalin model in the mouse. Following IACUC approval, mice were randomly pretreated with inert vehicle, ICI204448 1mg/kg, ICI204448 10mg/kg, CA1001 1mg/kg, or CA1001 10 mg/kg. Spontaneous nocifensive behaviors were blindly assessed (video recording). Neither agent was effective in reducing the acute (0-5 minutes) response to formalin injection (phase 1). CA1001 1 mg/kg was as effective as ICI204448 10 mg/kg in reducing formalin-induced responses at 20-35 minutes; CA1001 10 mg/kg was significantly more effective than ICI204448 10 mg/kg (phase 2; p