Korean J Physiol Pharmacol.  2015 Mar;19(2):125-130. 10.4196/kjpp.2015.19.2.125.

Effect of the Combination of CI-988 and Morphine on Neuropathic Pain after Spinal Cord Injury in Rats

• Kim J
• Kim Y
• Hahm SC
• Yoon YW

• KMID: 2285564
• DOI: http://doi.org/10.4196/kjpp.2015.19.2.125

Abstract

Cholecystokinin is known to be involved in the modulation of nociception and to reduce the efficacy of morphine analgesia. This study investigated the effects of intrathecal administration of morphine and the cholecystokinin type B antagonist CI-988 on below-level neuropathic pain after spinal cord injury in rats. We also examined the interaction of morphine and CI-988 in the antinociceptive effect. Both morphine and CI-988 given individually increased the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner. The combination of ineffective doses of intrathecally administered CI-988 and morphine produced significant analgesic effects and the combination of effective doses resulted in analgesic effects that were greater than the sum of the individual effects of each drug. Thus, morphine showed a synergistic interaction with CI-988 for analgesia of central neuropathic pain.

Keyword

Cholecystokinin; Morphine; Neuropathic pain; Spinal cord injury; Synergistic interaction

MeSH Terms

Analgesia
Animals
Cholecystokinin
Morphine*
Neuralgia*
Nociception
Rats*
Spinal Cord Injuries*
Cholecystokinin
Morphine

Figure

• 

  Fig. 1 Decreased paw withdrawal thresholds in SCI rats were significantly increased by IT morphine. (A) Effects of IT morphine on withdrawal threshold to mechanical stimulation applied to the plantar surface of the foot. Asterisks indicate significant difference from the pre-injection control value (PRE) (p<0.05). (B) Analgesic dose-response curve for morphine plotted at the time of peak effect (30 min). Results are expressed as percent (%) of the maximal effect.

• 

  Fig. 2 Decreased paw withdrawal thresholds in SCI rats were significantly increased by IT CI-988. (A) Time course of the effect of IT CI-988 on withdrawal threshold to mechanical stimulation applied to the plantar surface of the foot. Asterisks indicate significant difference from the pre-injection control value (PRE). (B) Analgesic dose-response curve for CI-988 plotted at the time of peak effect (15 min). Results are expressed as percent (%) of the maximal effect.

• 

  Fig. 3 The combination of CI-988 and morphine produced analgesic effects that were greater than the sum of the individual effects of each drug. (A) Time course of the effect of the combination of CI-988 and morphine on withdrawal threshold to mechanical stimulation applied to the plantar surface of the foot. The treatments administered were a combination of CI-988 and morphine at the following doses: CI-988:morphine ratios (in µg) of 97.1:2.9, 48.5:1.5, 19.4:0.6, and 9.7:0.3. Asterisks indicate significant difference from the pre-injection control value (PRE). (B) Analgesic dose-response curve for a combination of CI-988 and morphine plotted at the time of peak effect (15 min). Results are expressed as percent (%) of the maximal effect.

• 

  Fig. 4 Isobologram showing the effects of a combination of CI-988 and morphine on paw withdrawal threshold to mechanical stimulation. The dashed line represents the theoretical additive interaction. The interception of the dashed line on the ordinate and abscissa shows the observed ED50 values for morphine and CI-988 alone, respectively. The solid symbol represents the additive ED50(add) for the combination of CI-988 and morphine (97.1:2.9%). The actual ED50(mix) is represented by the open symbol. The standard errors for CI-988 and morphine are resolved into the corresponding components.

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