Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory nervous system. It is accompanied by neuronal and non-neuronal alterations, including alterations in intracellular second messenger pathways. Cellular levels of 3',5'-cyclic
adenosine monophosphate (cAMP) and 3',5'-cyclic
guanosine monophosphate (cGMP) are regulated by
phosphodiesterase (PDE)
enzymes. Here, we studied the impact of PDE inhibitors (PDEi) in a mouse model of
peripheral nerve injury induced by placing a cuff around the main branch of the sciatic nerve. Mechanical
hypersensitivity, evaluated using von Frey filaments, was relieved by sustained treatment with the non-selective PDEi
theophylline and
ibudilast (AV-411), with PDE4i
rolipram,
etazolate and
YM-976, and with PDE5i
sildenafil,
zaprinast and
MY-5445, but not by treatments with PDE1i
vinpocetine, PDE2i
EHNA or PDE3i
milrinone. Using pharmacological and knock-out approaches, we show a preferential implication of
delta opioid receptors in the action of the PDE4i
rolipram and of both mu and
delta opioid receptors in the action of the PDE5i
sildenafil.
Calcium imaging highlighted a preferential action of
rolipram on dorsal root ganglia non-neuronal cells, through PDE4B and PDE4D inhibition.
Rolipram had anti-neuroimmune action, as shown by its impact on levels of the pro-inflammatory
cytokine tumor necrosis factor-α (TNFα) in the dorsal root ganglia of mice with
peripheral nerve injury, as well as in human peripheral blood mononuclear cells (PBMCs) stimulated with
lipopolysaccharides. This study suggests that
PDEs, especially PDE4 and 5, may be targets of interest in the treatment of
neuropathic pain.