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New Kappa-Opioid Receptor Agonist Curbs Pain, Avoids Side Effects

July 5, 2016
Researchers in South Carolina are developing a kappa-opioid receptor agonist that avoids the side effects typical to mu-opioid receptor agonists, like addiction, while delivering pain relief akin to morphine.

Today, mu-opioid receptor agonists (MOR) are a common pharmacological options for treating chronic pain.

Unfortunately, these drugs also present side effects and risks, including nausea, vomiting, constipation, respiratory depression, and addiction. However, the development of an effective kappa-opioid receptor agonist (KOA) could be a promising alternative, one that may not be so far off.

Researchers at the South Carolina College of Pharmacy have begun the search for an orally-active KOA compound. Showing none of the adverse effects associated with undesired central activity or inadequate receptor selectivity, the research already has debuted 2 potential compounds that could be the impetus to a KOA-based analgesic, a drug that could curb chronic pain while steering clear of burdensome side effects.1

Using a variety of tests on lab rats, such as this acetic writhing assay (see figure 8), researchers were able to test the drug's pain-fighting capabilities.

Through application of JT Pharmaceuticals’s proprietary non-natural amino acid technology, the researchers produced 24 derivatives of Cara Therapeutics’s a D-amino acid tetrapeptide called CR665, a peripherally restricted KOA. According to Tyler C. Beck, an MD candidate at the Medical University of South Carolina (MUSC) and lead author of the study, the process was part of a long, controlled development process to design the most ideal chemical agent (Figure 1).

“Initially we made 18 derivatives, and we tested all 18 and then we picked 2 lead compounds to further pursue, and then we made further modifications on those to create our 19 through 24 derivatives with the intent of potentially generating a compound that was more potent an analgesic,” Mr. Beck told Practical Pain Management.

JT Pharma's proprietary technology enabled researchers to construct a chemically sound agent for testing.

Ultimately, Mr. Beck and his fellow researchers, including Thomas A. Dix, PhD, an associate professor at MUSC, settled on 2 promising derivatives that were uncovered in the initial batch – coded as JT07 and JT09. They conducted a series of pain tests on male Sprague Dawley rats (Harlan), comparing each compound individually to saline and morphine controls.

Both JT07 and JT09 compounds showed noticeable results in the acid pain writhing assay.

“JT09 ended up being very successful and as efficacious as morphine at alleviating peripheral pain, and we didn’t see any of the negative side effects associated with an opiate like morphine,” Mr. Beck reported.

During the hot plate assay, rats received JT07 and JT09 (20 mg/kg), while control rates received morphine (10 mg/kg) and were tested for centrally-mediated pain 20 minutes later. Researchers found the differences between JT07/JT09 and morphine in the measured percent maximum possible effect (%MPE) were stark – JT07/JT09 showed a %MPE at around 10%, compared to morphine’s 70% (Figure 8).

The new compounds showed stark differences in %MPE compared to morphine.

“The reason why there are so many negative side-effects associated with morphine is due to the fact that it agonizes opioid receptors in the brain, particularly the mu receptor,” which explained why the rats on morphine showed a 70% MPE of analgesia to the hot plate stimulus (Figure 9). “But our drug doesn’t cross the blood brain barrier (BBB), so we don’t agonize any of those opioid receptors in the brain,” which is why the rats on JT07/JT09 showed the opposite response, Mr. Beck explained.

A Non-addictive Analgesic?

Mr. Beck and his team performed a series of behavioral assessments on the rats, using analysis of variance (ANOVA) to test for any addictive qualities and dysphoria associated with their drug. Also in contrast to morphine, JT07 and JT09 appeared to lack an addictive quality.

The conditioned place preferences test.

In a conditioned place preference test, the researchers would alternate orally administering either JT07/JT09 or saline to see if the rats would associate the drug with a particular compartment (left or right), which can be a sign of addictive preference. However, JT07 and JT09 had no discernible effect when compared to baseline habituation preferences recorded before the drug was administered.

In the self-administration test, rats were given a 2 hour session each day to lever press for self-administration of JT09 or cocaine. From days 1 through 5, the rats failed to maintain lever pressing for JT09, while from days 6 to 12, the rats were robust in self-administration of cocaine. This test also suggested a lack of addictive potential in the compound, noticeably contrasting cocaine’s addictive effects (Figure 11).

The rats appeared to show no preference for JT09, suggesting the drug has no addictive qualities, whatsoever.

Lack of Dysphoria

Dysphoria, another undesired CNS-mediated activity associated with agonists like morphine, was tested through a forced swim assay, placing the rats in a tub of water and recording the amount of time (in seconds) the rats remained immobile over the last 4 minutes of each of the 4- to 6-minute trials (Figure 13).

The researchers administered another group of rats salvinorin A, a psychotropic molecule derived from Salvia divinorum. Like JT09, salvinorin A is a KOR-agonist, which is known to produce such effects as sedation, depression, and dysphoria.

Results of the forced swim assay.

However, JT09 appeared to lack any dysphoric effect when compared to salvinorin A. Rats given a single oral dose of JT09 (20 mg/kg) spent little time immobile in the water, while rats administered salvinorin A (0.3 mg/kg) spent up to 200 seconds immobile during the fourth trial.

“Essentially, when they become dysphoric, they would drown themselves if we didn’t yank them out of the tub. So they’re giving up on themselves, basically. Whereas with our compound, they exhibit normal rat behavior; they tried to escape the entire duration of all 4 trials that we ran on them,” Mr. Beck told Practical Pain Management.

Future Research

Mr. Beck and his team intend to continue researching JT09, assessing other known side-effect of MOR-agonists, like respiratory depression. “That was one of the major negative side effects associated with morphine that we weren’t able to test, but given the results of our previous experiments, we don’t expect to observe respiratory depression. We also want to test urinary output, just to confirm that this drug is not having any negative side effects associated with the kidney,” Mr. Beck told Practical Pain Management.

The researchers also have plans to test the toxicity of JT09, administering an average dosage level of the drug to the rats for 14 days straight. “We’re also going to dose rats with saline and morphine, and then after 14 days we’ll do a necropsy and we will analyze the rats’ tissue to observe if there is any gross abnormalities in the organ systems.”

According to Mr. Beck, the development of a peripherally-restrictive KOA-agonist could be a significant step towards the future of pain medicine.  “There has been limited studies on kappa opioid agonists so far, but from the studies that have been published, there seems to be less side effects associated with agonizing the kappa receptors. So that would definitely be a potential pharmaceutical for outpatient use if it’s peripherally-restricted.”

This work was supported by grants MH-65099 and NS-073378 from the National Institutes of Health to Dr. Dix. NIH also provided grant DA-36398 as subcontract from JT Pharmaceuticals. This research was presented as part of the American Academy of Pain Medicine’s annual meeting held in Orlando, Florida. No known conflicts of interest were reported by the authors of this study.

Last updated on: July 6, 2016
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