Effects of kappa opioid agonists alone and in combination with cocaine on heart rate and blood pressure in conscious squirrel monkeys

Abstract

As kappa agonists have been proposed as treatments for cocaine abuse, the cardiovascular effects of the kappa opioid receptor agonists ethylketocyclazocine (EKC) and enadoline were investigated in conscious squirrel monkeys. Both EKC and enadoline increased heart rate with little effect on blood pressure. This effect appeared to be specific for kappa receptors as the mu opioid agonist morphine did not mimic the effects of the kappa agonists. The opioid antagonist naltrexone, at a dose of 1.0 mg/kg, blocked the effect of EKC. An action at both central and peripheral receptors may be responsible for the heart rate increase following kappa agonist treatment. The ganglionic blocker chlorisondamine partially antagonized the effect of EKC on heart rate, suggesting central involvement, while the peripherally-acting agonist ICI 204,448 ((±)-1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) also increased heart rate, supporting a peripheral site of action. When given in combination with cocaine, EKC produced effects that were sub-additive, suggesting that the kappa agonists may be used safely as cocaine abuse treatments.

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

“…The selective κ OR antagonist nor‐binaltorphimine eliminated this effect indicating that the antiapoptotic effect of U50,488 was mediated via κ 1 OR activation. We recently confirmed their hypothesis using Q‐U50,488, which does not crosses the BBB …”

“…In Russia, this drug is used to treat stomach ulcers . We have shown that a quaternary analogue of the κ opioid agonist U‐50488 is another opioid that does not penetrate the BBB and is capable of increasing cardiac tolerance to I/R . Therefore, we suggest that those opioids, which are not able to activate the central ORs after systemic administration, might be most amenable to chronic use as cardioprotectants in high‐risk cases.…”

“…The antinecrotic effect of U50,488 is seen in the isolated heart. Recently, we have found that the quaternary ammonium salt of U50,488 (Q‐U50,488), which is not able to pass the BBB, elicits a protective effect against cardiac I/R injury . The infarct‐sparing effect of Q‐U50,488 was abolished by nor‐binaltorphimine implicating a peripheral κ OR.…”

Current Research on Opioid Receptor Function

“…Both the KOR agonists, ethylketocyclazocine and enadoline, elicited an increase heart rate with a little effect on blood pressure through a combined action on central and peripheral receptors in conscious squirrel monkeys that could be blocked by the opioid antagonist naltrexone. This effect appeared to be specific for KOR, since the MOR agonist morphine did not mimic the effects of the KOR agonists [287]. In addition, both DOR [172, 288] and KOR [172, 289] have been shown to mediate cardioprotection by preconditioning with myocardial ischemia and metabolic inhibition, one of the consequences of ischemia.…”