Replies to post #202810 on Biotech Values

[RockRat]

CARA presented preclinical data re abuse potential at a conference. Apparently it was well received.

>>INVESTIGATION OF THE DISCRIMINATIVE AND REINFORCING PROPERTIES OF THE K-OPIOID RECEPTOR AGONIST CR845 IN RATS


Smith SL, RenaSci Ltd, BioCity, Nottingham, NG1 1GF [e-mail]
Spencer R(1), Menzaghi F(1), Gosden J(2), Slater N(2), Holland SJ(2), Slade J(2), Heal DJ(2)
(1) Cara Therapeutics, Inc., 1 Parrott Drive, Shelton CT 06484; (2) RenaSci Ltd, BioCity, Nottingham NG1 1GF

CR845 is a peripherally-acting ?-opioid receptor agonist being developed to treat pain and pruritus. CR845 has no activity at µ- or d-opioid receptors. These studies investigated whether CR845 generalised to the discriminative cue elicited by the centrally acting mixed ?/s-receptor agonist and µ-receptor partial agonist, (-)pentazocine or substituted as a positive reinforcer in an intravenous self administration
(IVSA) experiment in heroin-maintained rats. Lister-Hooded female rats were trained to discriminate (-) pentazocine (5mg/kg ip) from saline. Butorphanol, a ?/µ opioid agonist, was selected as the reference comparator. Test drugs were tested 15min after iv injection. Results are reported as mean±SD percentage
generalisation to the (-)pentazocine cue. Sprague-Dawley, male, rats were trained to self administer heroin (0.015mg/kg/inj) on a FR5 schedule. After saline extinction, CR845 and (-)pentazocine were evaluated in separate groups of rats in 2 hour sessions. IVSA results are reported as mean±SEM. Drug-discrimination was validated by the dose dependent generalisation of iv (-)pentazocine (0.017 0.5 mg/kg,iv) to the training cue (17.7±8.9% to 75.8±8.2% [n=6]). The reference comparator, butorphanol (0.001–0.25 mg/kg iv), dose- dependently generalised to (-)pentazocine (17.1±11.7% to 76.6±17.5% [n=6/7]). CR845 (0.05, 0.125, 0.25, 0.5 mg/kg iv) generalised to saline at the lowest dose, (23.6±10.5% [n=7]) and partially generalised to (-) pentazocine at all other doses (35.4±20.2% [n=7], 31.0±17.9% [n=7], 34.5±10.1% [n=7], respectively) with no evidence of dose-dependence. Heroin-maintained IVSA in all rats (15.83±0.85 inj/session, n=13) that was signi cantly greater (p<0.001) than saline (3.65±0.37 inj/session, n=13). None of the doses of CR845 (0.001, 0.005, 0.025 or 0.125mg/kg/inj) maintained rates of IVSA at a level signi cantly greater than saline and all doses were signi cantly lower than heroin. (-)Pentazocine (0.03, 0.1 or 0.245mg/kg/inj) maintained IVSA at signicantly greater levels than saline. (-)Pentazocine and butorphanol both generalised fully to the
cue elicited by ip (-)pentazocine validating the model for detecting drugs with µ- and ?-agonist properties. CR845 produced low-level, non-dose-dependent, partial generalisation to (-)pentazocine. This result is consistent with the fact that CR845 is a potent ?-opioid receptor agonist with poor brain penetration. CR845 did not serve as a positive reinforcer in heroin-maintained rats. The reference comparator, (-)pentazocine, substituted for heroin in the model and served as a positive reinforcer across a range of doses. If these results translate into man, they predict that CR845 is unlikely to be recreationally abused by humans. Study funded by Cara Therapeutics Inc.<<

Abstract presented at British Association of Psychopharmacology

Regards, RockRat