Abstract
Upregulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in dorsal horn (DH) neurons has been causally linked to persistent inflammatory pain. This upregulation, demonstrated for both synaptic and extrasynaptic AMPARs, depends on the protein kinase C alpha (PKCα) activation; hence, spinal PKC inhibition has alleviated peripheral nociceptive hypersensitivity. However, whether targeting the spinal PKCα would alleviate both pain development and maintenance has not been explored yet (essential to pharmacological translation). Similarly, if it could balance the upregulated postsynaptic CP-AMPARs also remains unknown. Here, we utilized pharmacological and genetic inhibition of spinal PKCα in various schemes of pain treatment in an animal model of long-lasting peripheral inflammation. Pharmacological inhibition (pre- or post-treatment) reduced the peripheral nociceptive hypersensitivity and accompanying locomotive deficit and anxiety in rats with induced inflammation. These effects were dose-dependent and observed for both pain development and maintenance. Gene-therapy (knockdown of PKCα) was also found to relieve inflammatory pain when applied as pre- or post-treatment. Moreover, the revealed therapeutic effects were accompanied with the declined upregulation of CP-AMPARs at the DH synapses between primary afferents and sensory interneurons. Our results provide a new focus on the mechanism-based pain treatment through interference with molecular mechanisms of AMPAR trafficking in central pain pathways.
Highlights
Targeting the mechanisms underlying impairments for disease treatment is a concept of precision medicine for emerging advanced therapeutics with limited side effects
The postsynaptic AMPA receptors (AMPAR)-mediated currents were recorded in dorsal horn (DH) interneurons to assess whether PKCα inhibition arrested the inflammatory upregulation of CP-AMPARs at the DH synapses between primary afferents and sensory interneurons
This role originates from the activity-dependent trafficking of AMPARs, which balance has been broken in the DH interneurons in chronic pain conditions[5,7,8,12]
Summary
Targeting the mechanisms underlying impairments for disease treatment is a concept of precision medicine for emerging advanced therapeutics with limited side effects. Over decades of exploring the mechanisms of pain development and maintenance for effective interception of persistent pain at the cellular and molecular levels, glutamate AMPA receptors (AMPAR) are of a particular interest among various systems being outlined This is due to the principal role of AMPARs in fast transmission and because of AMPAR upregulation causing central sensitization of the dorsal horn (DH), a specific form of spinal plasticity mediating pain[1,2,3]. Our previous studies demonstrated that PKC antagonists[5,10] or genetic targeting the PKCα8 alleviated the inflammatory-induced nociceptive hypersensitivity Though it provides a proof-of-concept of targeting the spinal PKCα for pain relief, there has been, no systematic exploration of the therapeutic profile of such targeting to addressing both development and maintenance of persistent pain (essential for preclinical translation). The outcome of either pharmacological inhibition or gene-silencing approach on the inflammation-induced upregulation of CP-AMPARs at the DH synapses was demonstrated through recordings of the AMPAR-mediated postsynaptic currents evoked with primary afferent (dorsal root) stimulation in the superficial DH interneurons
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