PURINERGIC P2X3 AND P2Y1 RECEPTORS - OPPONENTS IN MYOFASCIAL NOCICEPTIVE PROCESSING

Introduction: Studies on myofascial pain apply α,ß-meATP as noxious agent due to its narrow receptor profile (P2X3) 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. Studies on myofascial pain apply α,ß-meATP as noxious agent due to its narrow receptor profile (P2X3) 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.

Methods: Noxious stimulation of semispinal neck muscles was performed by intramuscular (i.m.) bilateral injection of α,β-meATP or ATP (1 μmol/l, 20 μl) in anesthetized mice (n=40). 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 (MRS; 1 μmol/l, 20 μl) or the P2Y1 receptor agonist MeS-ADP (MeS; 1 μmol/l, 20 μl) were i.m. administered 20 min before ATP or two hours after α,β-meATP application, respectively. Noxious stimulation of semispinal neck muscles was performed by intramuscular (i.m.) bilateral injection of α,β-meATP or ATP (1 μmol/l, 20 μl) in anesthetized mice (n=40). 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 (MRS; 1 μmol/l, 20 μl) or the P2Y1 receptor agonist MeS-ADP (MeS; 1 μmol/l, 20 μl) were i.m. administered 20 min before ATP or two hours after α,β-meATP application, respectively.

Results: Injection of α,ß-meATP facilitated the reflex by 228.7±52.5% within two hours (F=11.4, p<0.001, n=10), whereas an effect was missing with ATP (n=10). With preceding administration of P2Y1 antagonist MRS, ATP induced reflex facilitation of 117.2±32.5% (X²=126.9, p<0.001, n=10). Subsequent injection of P2Y1 agonist MeS during established α,ß-meATP-evoked facilitation induced complete recovery down to baseline (X²=207.3, p<0.001, n=10). Injection of α,ß-meATP facilitated the reflex by 228.7±52.5% within two hours (F=11.4, p<0.001, n=10), whereas an effect was missing with ATP (n=10). With preceding administration of P2Y1 antagonist MRS, ATP induced reflex facilitation of 117.2±32.5% (X²=126.9, p<0.001, n=10). Subsequent injection of P2Y1 agonist MeS during established α,ß-meATP-evoked facilitation induced complete recovery down to baseline (X²=207.3, p<0.001, n=10).

Conclusion: P2Y1 blockade reveals excitatory ATP effects on P2X3 receptors. P2Y1 activation counteracts P2X3 excitation by α,ß-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. P2Y1 blockade reveals excitatory ATP effects on P2X3 receptors. P2Y1 activation counteracts P2X3 excitation by α,ß-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.