Cyclophosphamide induces NR2B phosphorylation-dependent facilitation on spinal reflex potentiation

Area of Science:

• Neuroscience
• Pharmacology
• Urology

Background:

• Cyclophosphamide (CYP) is known to sensitize pelvic afferent nerves, leading to suprapubic pain.
• The underlying mechanisms of CYP-induced visceral pain, particularly spinal neural plasticity, require further elucidation.

Purpose of the Study:

• To investigate if cyclophosphamide (CYP) induces visceral hyperalgesia/hypereflexia by promoting spinal activity-dependent neural plasticity.
• To compare pelvic-urethra reflex activity and spinal NR2B phosphorylation in rats treated with CYP versus a vehicle control.

Main Methods:

• Rats were treated with cyclophosphamide (CYP) or vehicle solution.
• Pelvic-urethra reflex activity and spinal N-methyl-D-aspartate receptor NR2B subunit (NR2B) phosphorylation in the lumbosacral dorsal horn were measured.
• Pharmacological antagonists (nitric oxide synthase and Cdk5 inhibitors) and small-interfering RNA for NR2B were employed.

Main Results:

• CYP treatment increased evoked spinal reflex potentiation and NR2B phosphorylation in the lumbosacral dorsal horn.
• Inhibition of nitric oxide synthase or Cdk5, or knockdown of NR2B, abolished CYP-induced reflex potentiation and NR2B phosphorylation.
• These findings indicate a role for NR2B phosphorylation in CYP-mediated spinal reflex potentiation.

Conclusions:

• Cyclophosphamide (CYP) facilitates spinal reflex potentiation through N-methyl-D-aspartate receptor (NMDAR) mediated pathways.
• Nitric oxide and Cdk5 signaling are involved in CYP-induced NR2B phosphorylation.
• These mechanisms contribute to the development of visceral hyperalgesia and hypereflexia.