PERIPHERAL AND SPINAL ACTIONS OF OPIOIDS BLOCKADE OF THE AUTONOMIC RESPONSE EVOKED BY COMPRESSION OF THE INFLAMED KNEE-JOINT

Background: Three types of opioid receptors, mu, delta, and kappa, are present in the periphery and in the central nervous system. In contra st to the effects in the central nervous system the antinociceptive ac tion of opioids in the periphery is not as well characterized. The eff ects of intraarticular, spinal, and intramuscular injections of mu, de lta, and kappa opioid agonists on the autonomic response evoked by com pression of an inflamed knee joint were evaluated. Methods: In halotha ne-anesthetized rats, arthritis was induced by injecting kaolin and ca rrageenan into the right knee joint. Standardized compression of the k nee joint by inflation of a pediatric blood pressure cuff to 200 mmHg for 2 min produced a reliable stimulus-dependent hypertension (Delta = 13 mmHg). Drugs were delivered intramuscularly, intrathecally through a chronic catheter, or intraarticularly into the right knee joint. Th e drug injection was performed 4 hr after induction of the inflammatio n. Results: The intrathecal administration of mu, delta, and kappa, ag onists resulted in a dose-dependent blockade of the cuff-evoked increa se in blood pressure. The order of intrathecal drug activity on the co mpression-evoked blood pressure responses with median effective dose ( ED(50)) was sufentanil (0.02 nmol; mu) > PD117302 (0.5 nmol; kappa); s piradoline (1.5 nmol; kappa) morphine (2.4 nmol; mu) > DADL) (15 nmol; delta; DPDPE (18 nmol; delta) > U-50,488H (620 nmol; kappa) > naloxon e = 0. The intraarticular administration of mu and kappa, but not delt a 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 mu mol)> PD117302 (0.3 mu mol); spiradoli ne (0.8 mu mol), morphine (0.9 mu mol) > U-50,488H (0.9 mu mol) > DPDP E(>5 mu mol); DADL (>18 mu mol) > nalosone = 0. Intramuscular injectio n of these agonists caused suppression, with the order of drug activit y (ED(50)) as follows: sufentanil (0.2 mu mol) > PD117302 (2 mu mol); spiradoline (11 mu mol) morphine (9 mu mol) > DPDPE (>5 mu mol); DADL (18 mu mol) > U-50,488H (22 mu mol) > naloxone = 0. All intraarticular effects were reversible by injecting naloxone intramuscularly, with t he ordering of naloxone potency against equiactive doses of morphine > U50,488H. Conclusions: The activity of the respective agonists and th e intraarticular > intramuscular ordering of systemic potency in this model indicate that opioids, by an action at mu and kappa can exert a direct antihyperalgesic action at the terminals of primary afferents p rojecting to a region of Inflammation. These observations offer strong support for a peripheral action of opioids in certain states In infla mmation-induced hyperalgesia.