Peripheral and spinal actions of opioids in the 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 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 intraarticular, spinal, and intramuscular injections of mu, delta, and kappa 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 joint. 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 (delta = 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 mu, delta, and kappa 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 (ED50) was sufentanil (0.02 nmol; mu) > PD117302 (0.5 nmol; kappa); spiradoline (1.5 nmol; kappa) morphine (2.4 nmol; mu) > DADL (15 nmol; delta); DPDPE (18 nmol; delta) > U-50,488H (620 nmol; kappa) > naloxone = 0. The intraarticular administration of mu and kappa, but not delta agonists, produced a dose-dependent blockade of a compression-evoked increase in blood pressure, with the order of drug activity (ED40) as follows: sufentanil (0.04 mumol) > PD117302 (0.3 mumol); spiradoline (0.8 mumol), morphine (0.9 mumol) > U-50,488H (0.9 mumol) > DPDPE (> 5 mumol); DADL (> 18 mumol) > naloxone = 0. Intramuscular injection of these agonists caused suppression, with the order of drug activity (ED50) as follows: sufentanil (0.2 mumol) > PD117302 (2 mumol); spiradoline (11 mumol) morphine (9 mumol) > DPDPE (> 5 mumol); DADL (18 mumol) > U-50,488H (22 mumol) > 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 respective agonists and the 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 projecting to a region of inflammation. These observations offer strong support for a peripheral action of opioids in certain states in inflammation-induced hyperalgesia.
Nagasaka
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Anesthesiology Research Laboratory, University of California, San Diego, La Jolla 92093-0818, USA.
Awad
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H
Yaksh
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TL
D000698:Analgesia; D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000503:physiopathology*; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D007270:Injections, Intra-Articular; D007273:Injections, Intramuscular; D007278:Injections, Spinal; D007719:Knee Joint; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000503:physiopathology; D010525:Peripheral Nerves / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology
D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone