Fig. 6.

Proposed schematic of cellular pathways involved in endogenous NPY and opioid synergistic pain inhibition. We propose that following initial pain resolution and the accompanying development of LS, endogenous ligand-dependent (NPY binding to Y1R) and ligand-independent (μ-opioid receptor constitutive activity, MOR_CA) interact in a synergistic manner to maintain LS in remission. However, this long-lasting Gα_i/o-coupled GPCR activity produces heterologous sensitization of AC1. We hypothesize that both MOR and Y1R share a common pool of AC1, thus, potent activation or blockade of either MOR_CA or Y1R signaling can prevent or produce a cAMP overshoot and the reinstatement of hyperalgesia, respectively. This idea is an extension of the work of Levitt et al. (52).