Sildenafil, a phosphodiesterase-5 inhibitor, enhances the antinociceptive effect of morphine.
Various evidence has demonstrated a role of the nitric oxide (NO)/cGMP signaling pathway in the processing of nociception. The exact role of phosphodiesterase-5 (PDE-5) via the NO/cGMP pathway is not fully understood in pain response. The aim of the present study was to investigate the possible peripheral interaction between a PDE-5 inhibitor (sildenafil) and morphine. Carrageenan-induced hyperalgesia in rats and the acetic-acid-induced writhing test in mice were used as animal models. Local administration of sildenafil (50-200 microg/paw, i.pl.) exhibited a dose-dependent antinociceptive effect against the paw pressure test. Sildenafil also demonstrated an antinociceptive effect (1-10 mg/kg, i.p.) against in the writhing test. Co-administration of sildenafil (100 microg/paw, i.pl. and 2 mg/kg, i.p.) significantly enhanced the antinociceptive effect of morphine (2 microg/ paw, i.pl. and 2 mg/kg, i.p respectively). The antinociception produced by the drugs alone or combined was due to a local action, as its administration in the contralateral paws was ineffective. Pretreatment with N(G)-nitro-L-arginine methyl ester (an NO synthesis inhibitor), methylene blue (gunalyl cyclase inhibitor) or naloxone (opioid receptor antagonist) blocked the effect of a sildenafil-morphine combination in both tests. The results suggest that opioid receptor (NO and cGMP) mechanisms are involved in the combined antinociceptive effect. Further, sildenafil produced antinociception per se and increased the response of morphine, probably through the inhibition of cGMP degradation.
Jain
Naveen K
NK
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Patil
C S
CS
Singh
Amarjit
A
Kulkarni
Shrinivas K
SK
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010147:Pain Measurement; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones; D013997:Time Factors
D000700:Analgesics; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009270:Naloxone; D009020:Morphine; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester