Potentiation of antinociceptive effects of morphine by calcium-channel blockers at the level of the spinal cord.
BACKGROUND
Opioids inhibit voltage-dependent calcium-channel conductance, which is essential for the nervous system to be able to signal a painful event. Accordingly, interference with calcium-channel conductance may enhance opioid analgesia. The current study was designed to investigate the effects of calcium-channel blocking drugs on the antinociception of morphine at the level of the spinal cord.


METHODS
Rats were chronically implanted with catheters in the lumbar intrathecal space. Tail-flick test was used to assess thermal nociception. Intrathecally administered drugs were morphine, calcium-channel blockers (verapamil, diltiazem, and nicardipine), or a combination of morphine and calcium-channel blocker.


RESULTS
Intrathecal administration of morphine produced a significant dose-dependent antinociception in the tail-flick test. In contrast, intrathecal administration of calcium-channel blockers, verapamil, diltiazem, and nicardipine, did not show any antinociception at the employed doses. However, when intrathecally administered calcium-channel blockers, verapamil (50 micrograms), diltiazem (100 micrograms), or nicardipine (20 micrograms), were combined with ineffective (0.25, 0.5, 1, or 2 micrograms) or moderately effective (5 micrograms) doses of intrathecally administered morphine, significant antinociception was produced. These interactions were synergistic. There were no significant changes in MAP or HR after the intrathecal administration of 200 micrograms verapamil or 2 micrograms morphine combined with 50 micrograms verapamil.


CONCLUSIONS
The authors interpreted these results to indicate that calcium-channel blocking drugs synergistically potentiate the analgesic effects of morphine at the level of the spinal cord. Before these results can be translated into clinical use, however, adequate toxicity studies must be conducted to examine the effect of the perispinal administration of calcium-channel blocking drugs on spinal cord function.
Omote
K
K
Department of Anesthesiology, Sapporo Medical College and Hospital, Japan.
Sonoda
H
H
Kawamata
M
M
Iwasaki
H
H
Namiki
A
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009529:Nicardipine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D009020:Morphine; D014700:Verapamil; D009529:Nicardipine; D004110:Diltiazem