Abstract
Painful axotomy decreases K
ATP
channel current (IK
ATP
) in primary afferent neurons. Because cytosolic Ca
2+
signaling is depressed in injured dorsal root ganglia (DRG) neurons, we investigated whether Ca
2+
–calmodulin (CaM)–Ca
2+
/CaM-dependent kinase II (CaMKII) regulates IK
ATP
in large DRG neurons. Immunohistochemistry identified the presence of K
ATP
channel subunits SUR1, SUR2, and Kir6.2 but not Kir6.1, and pCaMKII in neurofilament 200–positive DRG somata. Single-channel recordings from cell-attached patches revealed that basal and evoked IK
ATP
by ionomycin, a Ca
2+
ionophore, is activated by CaMKII. In axotomized neurons from rats made hyperalgesic by spinal nerve ligation (SNL), basal K
ATP
channel activity was decreased, and sensitivity to ionomycin was abolished. Basal and Ca
2+
-evoked K
ATP
channel activity correlated inversely with the degree of hyperalgesia induced by SNL in the rats from which the neurons were isolated. Inhibition of IK
ATP
by glybenclamide, a selective K
ATP
channel inhibitor, depolarized resting membrane potential (RMP) recorded in perforated whole-cell patches and enhanced neurotransmitter release measured by amperometry. The selective K
ATP
channel opener diazoxide hyperpolarized the RMP and attenuated neurotransmitter release. Axotomized neurons from rats made hyperalgesic by SNL lost sensitivity to the myristoylated form of autocamtide-2-related inhibitory peptide (AIPm), a pseudosubstrate blocker of CaMKII, whereas axotomized neurons from SNL animals that failed to develop hyperalgesia showed normal IK
ATP
inhibition by AIPm. AIPm also depolarized RMP in control neurons via K
ATP
channel inhibition. Unitary current conductance and sensitivity of K
ATP
channels to cytosolic ATP and ligands were preserved even after painful nerve injury, thus providing opportunities for selective therapeutic targeting against neuropathic pain.
