In muscle nociception, purinergic mechanisms play an important role. Studies on muscle pain typically apply a,b-meATP as noxious agent due to its narrow receptor profile (P2X3, P2X2/3) and sustained stability in tissue. In contrast, native ATP is quickly degraded to metabolites and interacts with excitatory P2X and inhibitory P2Y receptors. The experimental pharmacological study compares effects of both molecules in myofascial nociception in a model of neck muscle pain. Noxious stimulation of semispinal neck muscles was performed by intramuscular (i.m., 20 ml) bilateral injection of a,b- meATP (100 nM, 1mM) or native ATP (100 nM, 1 mM, 7.6 mM) in anesthetized mice (n=65). The impact of neck muscle noxious input on brainstem sensory processing was tested by the jaw-opening reflex elicited via electrical tongue stimulation. The P2Y1 receptor antagonist MRS2179 (1 mM, 20 ml) or the P2Y1 receptor agonist 2-MeSADP (1 mM, 20 ml) were i.m. administered 20 min before ATP or two hours after a,b-meATP application, respectively. Injection of a,b-meATP facilitated the reflex within two hours in a dose-dependent manner. In contrast, native ATP injection evoked facilitation only with low dosage (100 nM). Preceding blockade of P2Y1 receptors by MRS2179 revealed reflex facilitation even under high dosage of native ATP. Ongoing facilitation after injection of a,b-meATP was abolished by subsequent activation of P2Y1 receptors via 2- MeSADP. P2Y1 blockade reveals excitatory ATP effects on P2X receptors. P2Y1 activation counteracts P2X3 excitation by a,b-meATP. Results demonstrate opposing excitatory P2X3 and inhibitory P2Y1 effects of ATP in neck muscle nociceptive processing in mice. These mechanisms may be involved in the pathophysiology of neck muscle pain in man.