Acute Inhibition of Ca²⁺/Calmodulin-Dependent Protein Kinase II Reverses Experimental Neuropathic Pain in Mice

Abstract

The limited data that currently exist for the role of Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) in neuropathic pain are conflicting. In the present study, we tested the hypothesis that CaMKII is required for the maintenance of neuropathic pain in a rodent model of experimental mononeuropathy. Spinal nerve L 5 /L 6 ligation (SNL) was found to increase the spinal activity of CaMKII (pCaMKII) on the ipsilateral (but not contralateral) side. This effect was blocked by 2-[N-(2-hydroxyethyl)-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-Nmethylbenzylamine) (KN93) (intrathecal injection), a CaMKII inhibitor. Acute treatment with KN93 dose-dependently reversed SNL-induced thermal hyperalgesia and mechanical allodynia. The action of KN93 lasted for at least 2 to 4 h. 2-[N-(4-Methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-Nmethylbenzylamine (KN92) (45 nmol i.t.), an inactive analog of KN93, showed no effect on SNL-induced CaMKII activation, allodynia, or hyperalgesia. We further examined the pharmacologic action of trifluoperazine, a clinically used antipsychotic drug that we found to be a potent CaMKII inhibitor in these assays. Trifluoperazine (administered intraperitoneally or by mouth) dose-dependently reversed SNL-induced mechanical allodynia, thermal hyperalgesia, and CaMKII activation without causing locomotor impairment in mice at the highest doses used. In conclusion, our findings support a critical role of CaMKII in neuropathic pain. Blocking CaMKII or CaMKII-mediated signaling may offer a novel therapeutic target for the treatment of neuropathic pain.

Curcumin Attenuates Opioid Tolerance and Dependence by Inhibiting Ca2+/Calmodulin-Dependent Protein Kinase II α Activity

“…Although the beneficial actions of inhibiting the NMDA receptor (Trujillo and Akil, 1991;Gutstein and Trujillo, 1993) or CaMKIIa Tang et al, 2006b;Chen et al, 2009) in opioid tolerance, dependence, and in chronic pain have been unequivocally demonstrated and replicated by independent studies, little progress has been made in translating these findings to clinical use. In many attempts, drug toxicity was cited as a culprit for lack of success.…”

“…Although neuropathic pain and opioid tolerance and dependence are distinct central nervous system processes, they could potentially share a common contributor, such as synaptic long-term potentiation, for which CaMKIIa is required Lisman et al, 2012). Indeed, CaMKIIa has been found to be essential and required for chronic inflammatory pain (Luo et al, 2008), nerve injury-induced neuropathic pain (Chen et al, 2009), and opioid-induced hyperalgesia (Chen et al, 2010).…”

Genetic inactivation of calpain-1 attenuates pain sensitivity in a humanized mouse model of sickle cell disease

“…Inhibition of CaMKIIα, a calpain substrate 1 and an emerging player in sickle pain, also reversed neuropathic pain in mice. 15 Thus, it appears likely that calpain-1 activation under elevated calcium concentrations exacerbates sickle pain possibly by inhibiting mast cell activation and/or other mechanisms. Peripheral activation of mast cells in the skin, glial activation in the spinal cord, and central sensitization of the spinal dorsal horn neurons are known to contribute to chronic hyperalgesia in the Berkeley sickle mice.…”

Inhibition of CaMKII in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats

“…Mechanical sensitivity was assayed by the up-and-down paradigm using von Frey filaments (North Coast, San Jose, CA) according to the Dixon method (Luo et al, 2008;Chen et al, 2009). In brief, rats were individually placed into Plexiglas chambers over a mesh table and acclimated for 30 minutes before the test.…”