Abstract
Upregulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in the dorsal horn (DH) neurons of the spinal cord has been causally linked to the maintenance of persistent inflammatory pain. Therefore, inhibition of CP-AMPARs could potentially alleviate an, otherwise, poorly treatable chronic pain. However, a loss of CP-AMPARs could produce considerable side effects because of the crucial role of CP-AMPARs in synaptic plasticity. Here we have tested whether the inhibition of spinal CP-AMPARs with dicationic compounds, the open-channel antagonists acting in an activity-dependent manner, can relieve inflammatory pain without adverse effects being developed. Dicationic compounds, N1-(1-phenylcyclohexyl)pentane-1,5-diaminium bromide (IEM-1925) and 1-trimethylammonio-5-1-adamantane-methyl-ammoniopentane dibromide (IEM-1460) were applied intrathecally (i.t.) as a post-treatment for inflammatory pain in the model of complete Freund’s adjuvant (CFA)-induced long-lasting peripheral inflammation. The capability of dicationic compounds to ameliorate inflammatory pain was tested in rats in vivo using the Hargreaves, the von Frey and the open-field tests. Treatment with IEM-1460 or IEM-1925 resulted in profound alleviation of inflammatory pain. The pain relief appeared shortly after compound administration. The effects were concentration-dependent, displaying a high potency of dicationic compounds for alleviation of inflammatory hyperalgesia in the micromolar range, for both acute and long-lasting responses. The period of pain maintenance was shortened following treatment. Treatment with IEM-1460 or IEM-1925 changed neither thermal and mechanical basal sensitivities nor animal locomotion, suggesting that inhibition of CP-AMPARs with dicationic compounds does not give rise to detectable side effects. Thus, the ability of dicationic compounds to alleviate persistent inflammatory pain may provide new routes in the treatment of chronic pain.
Highlights
Persistent or chronic pain is a prominent healthcare problem worldwide, which is defined by the International Association for the Study of Pain (IASP) as a disease on its own, without apparent biological value that needs to be utterly eliminated after its appearance
Cumulative evidence indicates the key role of AMPA receptors (AMPARs) in central sensitization of the dorsal horn (DH), a specific form of plasticity in the spinal cord underlying the central mechanism by which peripheral pain develops and is maintained (Woolf and Salter, 2000; Ji et al, 2003)
Studies of the molecular mechanisms of persistent pain maintenance demonstrated the upregulation of CP-AMPARs either at the synapses (Hartmann et al, 2004; Vikman et al, 2008; Park et al, 2009) or at the extrasynaptic membranes of DH interneurons (Park et al, 2009; Kopach et al, 2011, 2013), both of those are causally linked to the maintenance of persistent inflammatory pain, since prevention of the CP-AMPAR upregulation in DH interneurons through targeted genetic interfering with the receptor trafficking machinery has effectively alleviated persistent inflammatory pain at the periphery (Park et al, 2009; Kopach et al, 2013)
Summary
Persistent or chronic pain is a prominent healthcare problem worldwide, which is defined by the International Association for the Study of Pain (IASP) as a disease on its own, without apparent biological value that needs to be utterly eliminated after its appearance. Chronic pain remains poorly treatable, attended with side effects and adaptation to a treatment, representing a growing clinical problem that requires new routes based on a mechanism-targeted therapy. Preventing the upregulation of CP-AMPARs in DH interneurons through the interference with molecular mechanisms of AMPAR trafficking has been demonstrated as an effective way to alleviate persistent inflammatory pain at the periphery (Park et al, 2009; Kopach et al, 2013). Inhibition of central receptors with genetic approaches remains restricted in practical treatment: the preferred focus is the use of conventional compounds
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
