Differential effects of spinal (R)-ketoprofen and (S)-ketoprofen against signs of neuropathic pain and tonic nociception: evidence for a novel mechanism of action of (R)-ketoprofen against tactile allodynia.
The spinal activity of racemic ketoprofen and its enantiomers in models of neuropathic and tonic pain was explored in rats. Tactile allodynia and thermal hyperalgesia were induced by tight ligation of the L(5)/L(6) spinal nerves. Tonic pain was modeled by the formalin-induced flinch response. The spinal injection of (S)-ketoprofen alone or of morphine alone did not produce antiallodynic activity. A 1:1 combination of these drugs produced a robust dose-dependent antiallodynic action, consistent with previous observations where (S)-ketorolac combined with morphine also produced antiallodynia. (R)-ketoprofen given alone spinally produced a dose-dependent antiallodynia, but its activity was not augmented by spinal morphine. Conversely, (S)-ketoprofen, but not (R)-ketoprofen, blocked the second phase of the formalin-induced flinch response; neither enantiomer significantly blocked phase one of the formalin response. Again, (S)-, but not (R)-ketoprofen, interacted synergistically with spinal morphine in suppressing the phase II formalin response. These results are consistent with a spinal COX inhibitory action of (S)-ketoprofen. These results also point to a novel, as yet undefined, mechanism of action of (R)-ketoprofen against signs of neuropathic pain that does not appear to involve COX inhibition. The ability to modulate tactile allodynia is of special interest as this represents an aspect of clinical neuropathic pain that is very difficult to treat adequately.
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA Sepracor, Inc., Marlborough MA 01752, USA.
M H
MH
Ossipov
T P
TP
Jerussi
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K
Ren
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H
Sun
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Porreca
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D007660:Ketoprofen / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009020:Morphine; D007660:Ketoprofen