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Norketamine (NKET) enantiomers in combination with morphine (MOR) for neuropathic pain
Author(s) -
Wala Elzbieta P,
Johnson Jaime K,
Crooks Peter A,
Dorfling LizeMari,
Holtman Joseph R
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a412-a
Subject(s) - neuropathic pain , nmda receptor , pharmacology , opioid , ketamine , medicine , morphine , analgesic , antagonist , anesthesia , hyperalgesia , opioid receptor , nociception , receptor
Neuropathic pain is a significant medical problem. The effectiveness of opioids is limited. NMDA receptor antagonists hold promise as drugs for neuropathic pain; however, the clinically useful NMDA receptor antagonists are limited. NMDA antagonism has been linked to an enhancement of opioid efficacy suggesting that an novel opioid‐NMDA antagonist combination may be effective. We have found that NKET, the major metabolite of ketamine (KET), has fewer side effects then KET. Little is known about the effectiveness of NKET‐opioid combination therapy so we have examined the effect of the enantiomers of NKET in combination with MOR in a rat model of neuropathic pain (chronic constriction nerve injury, CCI). Rats were treated (IP) with MOR, S(+)NKET and R(−)NKET alone as well as MOR plus S(+) or R((−)NKET on post CCI days 7, 9, 11, 14. The responsiveness to a mechanical noxious stimulus (32g/s) was determined using the paw‐pressure test. Maximum possible effect was calculated (%MPE). NKET enhanced [S(+) > R((−)], in a dose‐related fashion MOR analgesia. MOR (3mg/kg) + S(+)NKET (1mg/kg) was equipotent to 3‐ and 30‐fold higher doses of MOR (10mg/kg) or S(+)NKET (32mg/kg) alone (%MPE=100%). MOR (3mg/kg) + R((−)NKET (3mg/kg) was less potent (%MPE=65%). No side effects were observed for NKET + MOR (Rota rod). These data suggest that S(+)NKET + MOR (low dose) has analgesic efficacy with diminished side effects for each drug. Support: NIDA R‐42 DA017529 ‐02A1 (JRH) and KSEF‐949‐RDE‐008