Interaction between morphine and norketamine enantiomers in rodent models of nociception.

Abstract

Ketamine, one of a few clinically-available N-Methyl-D-aspartate (NMDA)-receptor antagonists, is known to improve the analgesic efficacy of opioids in humans and rodents. However, the use of ketamine in combination with opioids is mainly restricted to the perioperative setting, due to severe psychotomimetic, sedative and motor side effects. Recent data from our laboratory demonstrated that a major metabolite of ketamine, norketamine, in particular the S(+) enantiomer, had a better antinociception/side effects profile than ketamine in rats. It is unknown if norketamine affects opioid antinociception. In the present study, morphine (a low dose) was combined with S(+)- and R(-)-norketamine (sub-antinociceptive doses) and characterized utilizing rodent models of pain including: thermal nociception (the tail-flick test), peripheral neuropathy (chronic constriction nerve injury) and tonic inflammatory pain (the formalin test). The data showed that: 1) Norketamine enhanced morphine antinociception and blocked tolerance to this effect; 2) Norketamine potentiated morphine effectiveness in the alleviation of symptoms resulting from injury to nerve (mechanical hyperalgesia, tactile allodynia) and peripheral tissue (formalin-induced nociceptive behavior); 3) S(+)-norketamine was more potent than R(-)-norketamine; 4) Antinociception was not confounded by significant side effects. Morphine-S(+)-norketamine combination drug therapy may prove clinically useful for the alleviation of acute and chronic pain of differing etiology.

• Authors: Joseph R Holtman Jr, Peter A Crooks, Jaime Johnson-Hardy, Elzbieta P Wala
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 90 Issue 4 Pg. 769-77 (Oct 2008) ISSN: 0091-3057 [Print] United States
• PMID: 18582492 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Drug Combinations
• Excitatory Amino Acid Antagonists
• Formaldehyde
• Ketamine
• Morphine
• norketamine

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• Constriction, Pathologic (complications)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Interactions
• Drug Tolerance
• Excitatory Amino Acid Antagonists (chemistry, pharmacology)
• Formaldehyde
• Ketamine (analogs & derivatives, chemistry, pharmacology)
• Male
• Morphine (pharmacology)
• Motor Activity (drug effects)
• Pain (drug therapy, etiology)
• Pain Measurement (drug effects)
• Peripheral Nervous System Diseases (drug therapy, etiology)
• Physical Stimulation
• Postural Balance (drug effects)
• Rats
• Rats, Sprague-Dawley
• Reaction Time (drug effects)
• Stereoisomerism