Calcineurin (protein phosphatase 3, previously protein phosphatase 2B) plays a pivotal role in regulating activity-dependent synaptic plasticity in the brain. The development of neuropathic pain appears dependent upon some of the same mechanisms that underlie brain synaptic plasticity. Much progress has been made in elucidating some of these mechanisms but many gaps in our knowledge remain. As a result neuropathic pain continues to be inadequately treated. In this application we wish to fill in some of these gaps as we seek to elucidate whether calcineurin plays a role in regulating injury-elicited plasticity in the spinal dorsal horn. Our preliminary data revealed significantly lower calcineurin activity and content in the ipsilateral post-synaptic density (PSD) of spinal dorsal horn neurons in animals exhibiting neuropathic pain behavior following chronic constriction injury (CCI) of the sciatic nerve or spinal nerve ligation (SNL). The pain behavior after CCI was attenuated by an intrathecal injection of exogenous calcineurin. An intrathecal application of the calcineurin inhibitor FK-506 elicited pain behavior in control, uninjured animals. These data suggested a connection between calcineurin and neuropathic pain but it remains unclear how the loss of the phosphatase in the PSD may influence the development of neuropathic pain. In this application we postulate at least three negative consequences of calcineurin's loss. Disruption of a complex formed by the A kinase anchoring protein (AKAP), protein kinase A (PKA) and calcineurin (Aim 1). Persistent phosphorylation and insertion of AMPA receptors in the PSD membrane (Aim 2). Phosphorylation-dependent physical linking of AMPA, NMDA and metabotropic glutamate receptor (mGluR) families through the establishment or enhancement of links between the scaffolding proteins PSD-95, Shank and Homer (Aim 3). In addition, in the brain a loss of calcineurin activity at hippocampal synapses permits the transition from short to long-term memory. It is tempting to hypothesize that the transition to neuropathic pain is a consequence of the loss of calcineurin from the PSD of spinal dorsal horn neurons (Aim 4). Calcineurin activity in the PSD may critically constrain high-frequency afferent activity from eliciting long-lasting plasticity because the latter may signify the development of neuropathic pain. In other words, nerve injury may give rise to neuropathic pain at least in part as a result of the loss of calcineurin-mediated dephosphorylation in the spinal dorsal horn. With no dephosphorylation to prevent a remodeling of the PSD which favors synaptic enhancement only exaggerated evoked responses would be elicited by primary afferent activity. This enhanced sensory input manifests then as neuropathic pain. Overall we strive to achieve two goals. From a cellular perspective we wish to delineate the consequences of nerve injury on the protein matrix of the PSD in spinal dorsal horn neurons. From a therapeutic perspective we seek better target specificity for more effective analgesic treatments.
The processing of sensory information in the spinal dorsal horn may change significantly following peripheral nerve injury or inflammation to ultimately lead to the development of neuropathic pain. For example, a short but intense period of acute injury to the sciatic nerve may lead to persistent pain that far outlasts the initial insult. Much progres has been made in elucidating some of the mechanisms underlying the development of neuropathic pain. Yet, many gaps in our knowledge remain and as a result neuropathic pain continues to be inadequately treated. In this application we strive to achieve two goals. From a biological perspective we wish to fill in some of the gaps in our understanding of the mechanisms of neuropathic pain. From a therapeutic perspective we seek novel targets for more effective analgesic treatments.
|Miletic, Gordana; Lippitt, Jennifer A; Sullivan, Kristine M et al. (2013) Loss of calcineurin in the spinal dorsal horn contributes to neuropathic pain, and intrathecal administration of the phosphatase provides prolonged analgesia. Pain 154:2024-33|