TY032, AN OPIOID AGONIST AND NEUROKININ-1 RECEPTOR ANTAGONIST, MITIGATES NEUROPATHIC PAIN IN RODENTS

Jackie Hu , Alex James Sandweiss, Martin Kosar Faridian, Scott Robert Wallace, Aswini Kumar Giri, and Todd William Vanderah

TY032, AN OPIOID AGONIST AND NEUROKININ-1 RECEPTOR ANTAGONIST, MITIGATES NEUROPATHIC PAIN IN RODENTS

The release of excitatory neurotransmitter substance P (SP) is known to trigger pain signals when it binds to neurokinin-1 (NK-1) receptors. Inhibiting the activity of substance P can avert spontaneous pain signals to the brain. TY032 is a novel compound that is both an opioid agonist and an NK-1 antagonist. TY032 has been demonstrated to provoke analgesic activity through behavioral tests in rodent models while having significantly less unwanted side effects that are observed with an opioid alone, such as morphine. Spinal nerve ligation implemented on rats produced tactile allodynia and thermal hypersensitivity in the left hind paw. An intrathecal injection of the compound resulted in a maximal effect to the noxious infrared stimulus within 20 minutes. TY032 at doses in the low microgram range resulted in significant pain inhibition when tested with increasing thermal stimuli. Likewise, the Von Frey mechanical test revealed a maximal peak of paw withdrawal threshold indicating antiallodynia at approximately 80 minutes, followed by a return to basal levels by 180 minutes. In order to test for side effects, a 1 μg dosage of TY032 resulted in rats remaining on a rotating rod for a maximal time of 180 s. Thus, TY032 did not impair motor abilities or induce sedation. Naloxone was used to block endogenous opioid and TY032 opioid activity in tail flicking and flinching studies with mice to determine the activity of the NK-1 antagonism of the compound in substance P induced itching/biting. The mice were observed for flinches during a 5-minute period, where the group of mice with a vehicle/vehicle/SP (0.3 μg) injection resulted in substantially more flinches (19.43 ± 3.76) when compared to naloxone (1mg/kg)/ TY032 (3.0 μg)/ SP (0.3 μg) injection (4.86 ± 1.91), validating the compound as an NK-1 antagonist. The various behavioral tests achieved have indicated that TY032 hinders pain in a dose dependent mechanism by binding to μ- and δ-opioid receptors and acting as an agonist while also binding to the NK-1 receptors and acting as an antagonist. These studies demonstrate how novel compounds can be designed and synthesized to target different receptors and to act as either an agonist or antagonist that work together to inhibit pain while reducing unwanted side effects. This research is supported in part by funding from the UA Provost's Office and Dr. Vanderah’s lab.

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