Pain after
spinal cord injury (SCI) can be difficult to treat. Drugs that target the
opioid receptor (OR) outside the central nervous system (CNS) have gained increasing interest in
pain control owing to their low risk of central side effects.
Asimadoline and
ICI-204448 are believed to be peripherally restricted KOR agonists withlimited access to the CNS. This study examined whether they can attenuate
pain hypersensitivity in mice subjected to a contusive T10 SCI. Subcutaneous (s.c.) injection of
asimadoline (5, 20 mg/kg) and
ICI-204448 (1, 10 mg/kg) inhibited heat
hypersensitivity at both doses, but only attenuated mechanical
hypersensitivity at the high dose. However, the high-dose
asimadoline adversely affected animals' exploratory performance in SCI mice and caused aversion, suggesting CNS
drug penetration. In contrast, high-dose
ICI-204448 did not impair exploration and remained effective in reducing both mechanical and heat
hypersensitivities after SCI. Accordingly, we chose to examine the potential peripheral neuronal mechanism for ICI-204448-induced
pain inhibition by conducting in vivo
calcium imaging of dorsal root ganglion (DRG) in Pirt-GCaMP6s+/- mice. High-dose
ICI-204448 (10 mg/kg, s.c.) attenuated the increased fluorescence intensity of lumbar DRG neurons activated by a noxious pinch (400 g) stimulation in SCI mice. In conclusion, systemic administration of
ICI-204448 achieved SCI
pain inhibition at doses that did not induce notable side effects and attenuated DRG neuronal excitability which may partly contribute to its
pain inhibition. These findings suggest that peripherally restricted KOR agonists may be useful for treating SCI
pain, but the therapeutic window must be carefully examined.