J Korean Med Sci.  2008 Dec;23(6):1033-1038. 10.3346/jkms.2008.23.6.1033.

Additive Antinociception between Intrathecal Sildenafil and Morphine in the Rat Formalin Test

• Yoon MH
• Park KD
• Lee HG
• Kim WM
• An TH
• Kim YO
• Huang LJ
• Hua CJ

• KMID: 1107530
• DOI: http://doi.org/10.3346/jkms.2008.23.6.1033

Abstract

The possible characteristics of spinal interaction between sildenafil (phosphodiesterase 5 inhibitor) and morphine on formalin-induced nociception in rats was examined. Then the role of the opioid receptor in the effect of sildenafil was further investigated. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. For induction of pain, 50 microliter of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of drug interaction between sildenafil and morphine. Furthermore, naloxone was intrathecally given to verify the involvement of the opioid receptor in the antinociception of sildenafil. Both sildenafil and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. The isobolographic analysis revealed an additive interaction after intrathecal delivery of the sildenafil-morphine mixture in both phases. Intrathecal naloxone reversed the antinociception of sildenafil in both phases. These results suggest that sildenafil, morphine, and the mixture of the two drugs are effective against acute pain and facilitated pain state at the spinal level. Thus, the spinal combination of sildenafil with morphine may be useful in the management of the same state. Furthermore, the opioid receptor is contributable to the antinocieptive mechanism of sildenafil at the spinal level.

Keyword

Antinociception; Drug Interactions; Injections, Spinal; Phosphodiesterase 5 Inhibitor; Sildenafil; Morphine; Receptors, Opioid

MeSH Terms

Analgesics/*administration & dosage
Analgesics, Opioid/*administration & dosage
Animals
Behavior, Animal/drug effects
Dose-Response Relationship, Drug
Drug Synergism
Formaldehyde/toxicity
Injections, Spinal
Male
Morphine/*administration & dosage
Naloxone/administration & dosage
Narcotic Antagonists/administration & dosage
Pain/chemically induced/therapy
Pain Measurement/drug effects
Phosphodiesterase Inhibitors/*administration & dosage
Piperazines/*administration & dosage
Purines/administration & dosage
Rats
Rats, Sprague-Dawley
Sulfones/*administration & dosage
Time Factors

Figure

• 

  Fig. 1 Time effect curve of intrathecal sildenafil (A) and morphine (B) for flinching in the formalin test. Each drug was administered 10 min prior to the formalin injection. Formalin was injected subcutaneously at time 0. Data are presented as the number of flinches. Each line represents mean±SEM of 6-7 rats.

• 

  Fig. 2 Dose-response curve of intrathecal sildenafil and morphine for flinching in the formalin test. Data are presented as the percentage of control in phase 1 (A) and phase 2 (B). Sildenafil and morphine dose-dependently inhibited the flinches in both phases. Each line represents mean±SEM of 6-7 rats. C, control. *, p<0.05; †, p<0.01; ‡, p<0.001, compared with control.

• 

  Fig. 3 Isobologram for the interaction between intrathecal sildenafil and morphine during phase 1 (A) and phase 2 (B) in the formalin test. The ED50 values for each agent are plotted on the x- and y- axes, respectively. Horizontal and vertical bars indicate confidence intervals. The straight line connecting each ED50 value is the theoretical additive line and the point on this line is the theoretical additive ED50 (T). The experimental ED50 (E) was not significantly different from T, indicating an additive interaction. Each point on the graph represents ED50 values from dose-response curves including 20-24 rats.

• 

  Fig. 4 The antagonistic effects of intrathecal naloxone (0.3 µg) for the antinociception of intrathecal sildenafil (30 µg) in the formalin test. Naloxone was administered 10 min prior to the injection of formalin. Naloxone alone had little effect on the control response with formalin (A). Naloxone reversed the effect of sildenafil during phase 1 (B) and phase 2 (C) of the formalin test. Data are presented as the percentage of control. Each bar represents mean±SEM of 5 rats. *, p<0.05, compared with control.

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