In vivo activation of the SK channel in the spinal cord reduces the NMDA receptor antagonist dose needed to produce antinociception in an inflammatory pain model.

N-methyl-D-aspartate receptor (NMDAR) antagonists have been shown to reduce mechanical hypersensitivity in animal models of inflammatory pain. However, their clinical use is associated with significant dose-limiting side effects. Small-conductance Ca-activated K channels (SK) have been shown to modulate NMDAR activity in the brain. We demonstrate that in vivo activation of SK channels in the spinal cord can alleviate mechanical hypersensitivity in a rat model of inflammatory pain. Intrathecal (i.t.) administration of the SK channel activator, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309), attenuates complete Freund adjuvant (CFA)-induced mechanical hypersensitivity in a dose-dependent manner. Postsynaptic expression of the SK channel subunit, SK3, and apamin-sensitive SK channel-mediated currents recorded from superficial laminae are significantly reduced in the dorsal horn (DH) after CFA. Complete Freund adjuvant-induced decrease in SK-mediated currents can be reversed in vitro by bath application of NS309. In addition, immunostaining for the SK3 subunit indicates that SK3-containing channels within DH neurons can have both somatic and dendritic localization. Double immunostaining shows coexpression of SK3 and NMDAR subunit, NR1, compatible with functional interaction. Moreover, we demonstrate that i.t. coadministration of NS309 with an NMDAR antagonist reduces the dose of NMDAR antagonist, DL-2-amino-5-phosphonopentanoic acid (DL-AP5), required to produce antinociceptive effects in the CFA model. This reduction could attenuate the unwanted side effects associated with NMDAR antagonists, giving this combination potential clinical implications.

Peripheral metabotropic glutamate receptors as drug targets for pain relief.

The relatively new family of G-protein-coupled metabotropic glutamate receptors (mGluRs) is comprised of eight cloned subtypes, which are classified into three groups based on their sequence homology, signal transduction mechanisms and receptor pharmacology. It is now well-established that mGluRs in the central nervous system are essential for neuroplasticity associated with normal brain functions but are also critically involved in various neurological and psychiatric disorders. Recent anatomical and behavioural evidence suggests an important role of mGluRs in peripheral tissues in animal models of inflammatory and neuropathic pain. Once the cellular effects of peripheral mGluR activation and inhibition are better understood, certain peripheral mGluR subtypes may become important novel therapeutic targets for the relief of pain associated with peripheral tissue injury. Peripherally acting drugs that modulate nociceptive processing through mGluRs should have the advantage of lacking the central side effects commonly observed with drugs interfering with glutamatergic transmission in the central nervous system.

Localization of CaMKIIalpha in rat primary sensory neurons: increase in inflammation.

This study investigates Ca(2+)/calmodulin kinase IIalpha (CaMKIIalpha) in primary sensory neurons. Immunohistochemical staining with a CaMKIIalpha antibody demonstrates 28% of dorsal root ganglion (DRG) cells are positively stained and have a diameter of 27 +/- 2.4 microm (mean +/- S.D.). Placement of tight ligatures around the sciatic nerve demonstrates a build up of immunoreaction product proximal to the ligatures indicating that CaMKIIalpha is transported into the peripheral processes of DRG cells. Immunostaining of lumbar dorsal roots at the electron microscopic level demonstrates reaction product in 15.4 +/- 2.1% of unmyelinated and 2.4 +/- 1.0% of myelinated axons, indicating that CaMKIIalpha is transported into the central processes of DRG cells. Electron microscopic analysis of normal digital nerves demonstrates CaMKIIalpha labeling in 3.3 +/- 0.3% of unmyelinated and 2.0 +/- 1.1% of myelinated cutaneous axons. These percentages increase significantly to 14.1 +/- 2.3% for unmyelinated and 5.1 +/- 1.4% for myelinated axons 48 h after complete Freund's adjuvant-induced inflammation of the hindpaw. The data indicate that CaMKIIalpha is present in small diameter primary sensory neurons, that it is transported into the peripheral and central processes of these cells and may play a role in processing noxious input, particularly in the inflamed state.