Long-term Activation of Spinal Opioid Analgesia After Inflammation

Tissue injury sensitizes the peripheral and central mechanisms that drive ongoing pain and hyperalgesia. An opposing mechanism of intrinsic relief from acute pain involves endogenous activation of the ì-opioid receptor (MOR). It is widely assumed that pain inhibition is no longer needed when tissues heal, as ongoing peripheral nerve activity subsides and NMDA-mediated central sensitization weakens. However, we have obtained new data suggesting that endogenous opioidergic signaling persists for months to oppose the transition from acute to chronic pain. We discovered that, by giving an intrathecal injection of opioid receptor antagonist naltrexone (NTX) after the resolution of inflammation-induced hyperalgesia, we could reinstate not only hyperalgesia and spontaneous pain, but also pERK expression, neuronal Ca2+ mobilization, and cAMP overshoot in the spinal cord. These novel findings provide us with an opportunity to explore the facilitatory signaling mechanisms that maintain the pain memory trace, and the inhibitory opioidergic mechanisms that suppress it. Our overall hypothesis is that peripheral inflammation induces prolonged spinal engagement of pronociceptive NMDA receptor activation of adenylyl cyclase 1 (AC1) (Aim 1), which is counterbalanced by constitutive (agonist-independent) mu opioid receptor activity, which we term MORCA (Aim 2). We hypothesize that these findings in mice will translate to clinical post-operative pain (Aim 3). We further reason that, with time, enhanced basal MOR signaling produces cellular dependence. Our long-term goal is to determine whether MORCA dependence and latent (or quiescent) NMDA-R–AC1 sensitization creates a lasting susceptibility to develop chronic pain.