Characterization of dynorphin A-induced antinociception at spinal level.
Dynorphin A (DYN A) injected intrathecally in the rat produced a significant elevation of the nociceptive threshold, measured by the tail flick test. The highest dose of DYN A (25 nmol) produced maximal elevation of tail flick latency to radiant heat together with hindlimb paralysis and tail flaccidity lasting several hours, thus confirming several previous reports. A lower dose of DYN A (12.5 nmol) produced only a smaller, not constant, short-lasting change in the nociceptive threshold. The vocalization test (electrical stimulation of the tail) gave a different result: the time course curve showed that the antinociceptive effect had worn off 60 min after DYN A 25 nmol. Thus it can be assumed that the prolonged depression of the tail flick reflex was related to motor dysfunction and did not completely reflect the animal's response to painful stimuli. Tolerance to the antinociceptive and motor effects developed after the chronic intrathecal infusion of DYN A with osmotic minipumps. Intrathecal MR 1452 (30 nmol), a purported kappa-receptor blocker, fully prevented the effects of DYN A but not morphine-induced antinociception. Naloxone antagonized DYN A only at a 4 fold higher dose. MR 1452 (90 nmol) administered after DYN A reversed the elevation of the vocalization threshold while tail flick latency remained unmodified. Analysis by high performance liquid chromatography of intrathecally injected radiolabelled DYN A revealed that DYN A was largely broken down about 10 min after its administration. Our results seem to indicate that DYN A in the spinal cord causes alterations in nociception and motor function, clearly distinguishable in time and both mediated by an opioid receptor, probably of the kappa type. However, different mechanism(s), possibly non-opioid in nature, may contribute to the prolonged depression of the tail flick.
Spampinato
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Candeletti
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D000698:Analgesia; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D004361:Drug Tolerance; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D012684:Sensory Thresholds / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
D001575:Benzomorphans; D009270:Naloxone; C029552:Mr 1452; D004399:Dynorphins