Inhibition of nNOS prevents and inhibition of iNOS reverses α,β-meATP-induced facilitation of neck muscle nociception in mice

Infusion of α,β-methylene ATP (α,β-meATP) into murine neck muscle facilitates brainstem nociception. Unspecific nitric oxide synthase (NOS) inhibition prevents and reverses this sensitization. It is unclear whether neuronal (nNOS), inducible (iNOS) or endothelial NOS isoenzymes are involved in this α,β-meATP effect. Hypothesized involvement of nNOS isoenzyme was addressed by preceding (0.5, 1, and 2 mg/kg) and subsequent (2 mg/kg) intraperitoneal injection of the nNOS-inhibitor NPLA. iNOS involvement was addressed by subsequent, intraperitoneal administration of the iNOS-inhibitor 1400 W (2 mg/kg). Brainstem nociception was monitored by the jaw-opening reflex elicited via electrical tongue stimulation in 45 anesthetized mice. Preceding NPLA dose-dependently prevented α,β-meATP-induced reflex facilitation. Whereas subsequent inhibition of nNOS showed no effect, iNOS inhibition by 1400 W significantly reversed reflex facilitation. Data provide evidence that nNOS plays a major role in induction and iNOS in maintenance of facilitation in neck muscle nociception. Divergent roles of NOS isoenzymes may promote research on target specific treatment for headache and neck muscle pain.