Peripheral and spinal actions of opioids in the blockade of the autonomic response evoked by compression of the inflamed knee joint

Abstract

Background: Three types of opioid receptors, μ, δ, and κ, are present in the periphery and in the central nervous system. In contrast to the effects in the central nervous system, the antinociceptive action of opioids in the periphery is not as well characterized. The effects of intracellular, spinal, and intramuscular injections of μ, δ, and κ opioid agonists on the autonomic response evoked by compression of an inflamed knee joint were evaluated. Methods: In halothane-anesthetized rats, arthritis was induced by injecting kaolin and carrageenan into the right knee join. Standardized compression of the knee joint by inflation of a pediatric blood pressure cuff to 200 mmHg for 2 min produced a reliable stimulus-dependent hypertension (Δ = 13 mmHg). Drugs were delivered intramuscularly, intrathecally through a chronic catheter, or intraarticularly into the right knee joint. The drug injection was performed 4 hr after induction of the inflammation. Results: The intrathecal administration of μ, δ, and κ agonists resulted in a dose- dependent blockade of the cuff-evoked increase in blood pressure. The order of intrathecal drug activity on the compression-evoked blood pressure responses with median effective dose (ED 50) was sufentanil (0.02 nmol; μ) > PD117302 (0.5 nmol; κ); spiradoline (1.5 nmol: κ) morphine (2.4 nmol; μ) > DADL (15 nmol; δ); DPDPE (18 nmol; δ) > U-50,488H (620 nmol; κ) > naloxone = 0. The intraarticular administration of μ and κ, but not δ agonists, produced a dose-dependent blockade of a compression-evoked increase in blood pressure, with the order of drug activity (ED 50) as follows: sufentanil (0.04 μmol) > PD117302 (0.3 μmol); spiradoline (0.8 μmol), morphine (0.9 μmol) > U-50,488H (0.9 μmol) > DPDPE (>5 μmol); DADL (>18 μmol) naloxone = 0. Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED 50) as follows: sufentanil (0.2 μmol) > PD117302 (2 μmol); spiradoline (11 μmol) morphine (9 μmol) > DPDPE (>5 μmol); DADL (18 μmol) > U-50,488H (22 μmol) > naloxone = 0. All intraarticular effects were reversible by injecting naloxone intramuscularly, with the ordering of naloxone potency against equiactive doses of morphine > U50,488H. Conclusions: The activity of the perspective agonists and the intraarticular > intramuscular ordering of systemic potency in this model indicate that opioids, by an action at μ and κ, can exert a direct antihyperalgesic action at the terminals of primary afferents projecting to a region of inflammation. These observations offer strong support for a peripheral action of opioids in certain states in inflammation-induced hyperalgesia.