Background and objective: The cyclic guanosine monophosphate level, which causes an antinociception, is increased in cells as a direct result of phosphodiesterase inhibition. This study used a nociceptive test to examine the nature of the pharmacological interaction between intrathecal zaprinast, a phosphodiesterase inhibitor, and morphine. Methods: Catheters were inserted into the intrathecal space through an incision in the atlantooccipital membrane of male Sprague–Dawley rats. As a nociceptive model, 50 μL of a 5% formalin solution was injected into the hind paw. After observing the effect of zaprinast (37, 111, 369 nmol) and morphine (1, 4, 10, 40 nmol) alone, the interactions of their combination were examined by an isobolographic analysis. Results: Intrathecal zaprinast (P < 0.05) and morphine (P < 0.05) dose-dependently suppressed the flinching observed during phase 1 and phase 2 in the formalin test. The ED50 values (95% confidence intervals) of zaprinast and morphine in phase 1 were 161.9 (87.9–298.3) and 11.6 nmol (4.8–27.9 nmol), respectively. The phase 2 ED50 values (95% confidence intervals) of zaprinast and morphine were 229.9 (142.5–370.9) and 3.9 nmol (1.9–7.6 nmol), respectively. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery a zaprinast–morphine mixture in both phases. The ED50 values of (95% confidence intervals) zaprinast in the combination of zaprinast with morphine in phase 1 and phase 2 were 14.2 (4.9–40.6) and 10.4 nmol (3–35.9 nmol), respectively. Conclusions: Intrathecal zaprinast and morphine are effective against acute pain and facilitated pain state. Zaprinast interacts synergistically with morphine.