There is an overwhelming need for research leading to a greater understanding of central nervous system mechanisms that regulate the transition from acute to chronic pain. The Institute of Medicine states that 116 million Americans are burdened with chronic pain, costing over $600 billion annually. While opioid medications are commonly prescribed to treat pain, they are only moderately efficacious, and adverse side effects and potential for abuse stress the need for greater understanding of their analgesic mechanisms. A large body of research indicates that peripheral inflammation initiates maladaptive plasticity within the spinal cord and brain, termed central sensitization-that contributes to chronic pain. Less appreciated, however, are data which suggest that central sensitization far outlasts overt signs of pain sensitivity, in a silent form termed "latent central sensitization" (LCS). This proposal is innovative in that it suggests a novel molecular mechanism of LCS;the central hypothesis is that inflammation produces an adenylyl cyclase 1 (AC1)- and AMPA receptor (AMPAR)-dependent LCS that is masked by spinal opioid receptors. This hypothesis will be tested with three specific aims:
AIM 1 tests the hypothesis that tonic mu opioid receptor (MOR) activity decreases dorsal horn AMPAR-mediated Ca2+ signaling during long-lasting LCS after injury.
Aim 1 uses innovative real-time Ca2+ imaging in adult spinal dorsal horn (DH) slices to determine whether opioid receptor blockade increases AMPAR-mediated DH Ca2+ signaling.
AIM 2 tests the hypothesis that AMPAR subunit GluA2 phosphorylation and internalization maintains LCS.
Aim 2 will test this hypothesis by measuring GluA2 Ser880 phosphorylation and internalization in the presence or absence of NTX.
AIM 3 tests the hypothesis that injury-induced long- term increases in GluA2 internalization and Ca2+ permeability are maintained by AC1 activity. In DH from mice with AC1 deletion or pharmacological inhibition, Aim 3 will compare AMPAR-mediated Ca2+ responses and determine total and phosphorylated GluA2 and cell surface expression in the presence or absence of opioid receptor blockade. The proposed research is significant because if our hypotheses are correct, then any event that interferes with opioid receptor activity could unleash pronociceptive AC1-AMPAR signaling, and thus allow the transition to chronic pain. The results and concepts generated in this proposal may lead to a vertical leap in our understanding of pain vulnerability after tissue inflammation, and has the long-term potential to reveal novel targets to prevent the transition from acute to chronic pain.
Chronic pain management is a major scientific and public health care challenge, as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that injury triggers the development of a vicious cycle spinal of neuronal signaling that maintains sensitivity to pain long after tissue healing;ths is chronically masked by the body's naturally occurring pain inhibitory system that involves opioid receptors. Our studies aim to reveal the neurochemical mechanisms that maintain this vicious cycle of pain signaling. This project is relevant to NIH's mission that pertains to fundamental processes driving the transition from acute to chronic pain, and promotes the development of therapeutic interventions for pain management.