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

Abstract

Opioid-induced hyperalgesia (OIH) is a less-studied phenomenon that has been reported in both preclinical and clinical studies. Although the underlying cause is not entirely understood, OIH is a real-life problem that affects millions of patients on a daily basis. Research has implicated the important contribution of Ca 21 / calmodulin-dependent protein kinase IIa (CaMKIIa) to OIH at the level of spinal nociceptors. To expand our understanding of the entire brain circuitry driving OIH, in this study we investigated the role of CaMKIIa in the laterocapcular division of the central amygdala (CeLC), the conjunctive point between the spinal cord and rostro-ventral medulla. OIH was produced by repeated fentanyl administration in the rat. Correlating with the development of mechanical allodynia and thermal hyperalgesia, CaMKIIa activity was significantly elevated in the CeLC in OIH. In addition, the frequency and amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) in CeLC neurons were significantly increased in OIH. 2-[N-(2-hidroxyethyl)-N-(4-methoxybenzenesulfonyl)]-amino-N-(4-chlorocinnamyl)-N-methylbenzylamine, a CaMKIIa inhibitor, dose dependently reversed sensory hypersensitivity, activation of CeLC CaMKIIa, and mEPSCs in OIH. Taken together, our data for the first time implicate a critical role of CeLC CaMKIIa in OIH.

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

“…Chemicals other indicated were obtained from Beyotime and Boster (Shanghai, China). Four times injections of fentanyl (60 μg/kg per injection, s.c.) at 15 min intervals, resulting in a cumulative dose of 240 μg/kg [10, 11] were conducted to induce OIH in this study. The control animals received an equal volume (1.2 ml/kg) of physiological saline.…”

“…The interval between adjacent tests was more than 5 minutes. The 50% probability of paw withdrawal threshold was calculated using the up and down paradigm [11, 36, 37]. …”

“…The cutoff was 15 s to prevent damaging of tissues. The test was repeated three trials with a 5-minute interval, and then the thermal latency was defined as the mean of three trials [11]. …”

“…Although the underlying mechanism of OIH is not yet completely understood[1, 3, 4, 10], previous reports from our groups have shown that CaMKIIα, which is highly expressed in the CeLC and superficial spinal dorsal horn, plays an important role in modulation of OIH[11, 12]. Either spinal or CeLC CaMKIIα inhibition can attenuate OIH [11, 12]. The descending pain modulation from the periaqueductal gray (PAG) and rostral ventromedial medulla(RVM) has clearly been involved in the development of hyperalgesia and analgesic tolerance induced by opiates [13–16].…”

“…In our previously experiment, we have found that detectable mechanical and thermal behavioral hyperalgesia peaked at 6.5 h post fentanyl injection, and lasted for 3 d-4 d [11]. Therefore, 6.5 h post fentanyl injection, the CaMKIIα inhibitor KN93 was micro-infused into CeLC, spinal cord and PAG respectively to evaluate its effect on behavioral hyperalgesia and the activity of CaMKIIα at different level of the CeLC-PAG-RVM-spinal cord descending pathway.…”