Korean J Pain.  2005 Dec;18(2):99-106. 10.3344/kjp.2005.18.2.99.

Antinociceptive Effect of the Intrathecal Phosphodiesterase Inhibitor, Zaprinast, in a Rat Formalin Test

• Heo BY
• Kim CM
• Jeong ST
• Kim SJ
• Choi JI
• Yoon MH

• KMID: 2277970
• DOI: http://doi.org/10.3344/kjp.2005.18.2.99

Abstract

BACKGROUND
Cyclic guanosine monophosphate (cGMP) and opioid receptors are involved in the modulation of nociception. Although the opioid receptors agonists are active in pain, the effect of an phospodiesterase inhibitor (zaprinast) for increasing the level of cGMP has not been thoroughly investigated at the spinal level. This study examined the effects of intrathecal zaprinast and morphine in a nociceptive test and we also examined the nature of the pharmacological interaction after the coadministration of zaprinast with morphine. The role of the nitric oxide(NO)-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. METHODS: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, 50microliter of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of the drug interaction between zaprinast and morphine. Furthermore, NO synthase inhibitor (L-NMMA), guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide) were intrathecally administered to verify the involvement of the NO-cGMP-potassium channel pathway on the antinociception effect of zaprinast. RESULTS: Both zaprinast and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after the intrathecal administration of the zaprinast-morphine mixture in both phases. Intrathecal L-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase. CONCLUSIONS: These results suggest that zaprinast, morphine and the mixture of the two drugs are effective against acute pain and they facilitated pain state at the spinal level. Thus, the spinal combination of zaprinast with morphine may be useful for the management of pain. However, the NO-sensitive cGMP-potassium channel pathway did not contribute to the antinocieptive mechanism of zaprinast in the spinal cord.

Keyword

antinociception; interaction; morphine; NO-cGMP-potassium channel pathway; spinal cord; zaprinast

MeSH Terms

Acute Pain
Animals
Catheters
Drug Interactions
Formaldehyde*
Glyburide
Guanosine Monophosphate
Guanylate Cyclase
Humans
Male
Morphine
Nitric Oxide Synthase
Nociception
omega-N-Methylarginine
Pain Measurement*
Potassium Channels
Rats*
Receptors, Opioid
Spinal Cord
Formaldehyde
Glyburide
Guanosine Monophosphate
Guanylate Cyclase
Morphine
Nitric Oxide Synthase
Potassium Channels
Receptors, Opioid
omega-N-Methylarginine