Activation of Spinal Cholecystokinin and Neurokinin-1 Receptors Is Associated With the Attenuation of Intrathecal Morphine Analgesia Following Electroacupuncture Stimulation in Rats

Abstract

Abstract. We previously demonstrated that electroacupuncture (EA) stimulation both produced antinociception and attenuated intrathecal (i.t.) morphine analgesia, suggesting that EA is capable of inducing two opposing systems, that is, opioid and anti-opioid mechanisms. This study examined the involvement of cholecystokinin (CCK) in the anti-opioid effects following EA in the spinal cord. EA was applied to commonly used acupoints for antinociception, ST-36 located 5-mm lateral to the anterior tubercle of the tibia, and analgesia was assessed by the hind-paw pressure test in male Sprague-Dawley rats. I.t. administration of CCK (0.01 -10 µg) attenuated i.t. morphine analgesia (10 µg) dose-dependently. The attenuation of morphine analgesia following EA was reversed by i.t. proglumide, a CCK-receptor antagonist (0.01 µg). CCK-like immunoreactivity was increased in lamina I and II in the dorsal horn, and expression of spinal CCK mRNA increased after EA. Moreover, i.t. pretreatment with the neurokinin-1 (NK1)-receptor antagonist L-703,606 (18 µg) reversed both EA-and CCK-induced attenuation of morphine analgesia. These results suggest that CCK-mediated neural systems in the spinal cord may be involved in the attenuation of morphine analgesia following EA and that substance P-induced activation of NK1 receptors may be responsible for the downstream neuronal transmission of the CCK-mediated neuronal system.

The roles of nerve growth factor and cholecystokinin in the enhancement of morphine analgesia in a rodent model of central nervous system inflammation

“…A 1.0 ng dose of CCK-8S was used, and CCK-8S or vehicle (0.9% saline) was co-administered with morphine. Consistent with the results of Fukazawa et al (2007) and as observed in our pilot studies, this dose of CCK-8S was a low dose that did not affect the antinociception produced by 3 μg i.t. morphine in naïve rats.…”

“…administration of CCK-8S attenuated the effects of morphine in animals with carrageenan inflammation (but not in normal animals), the present results show that a low dose of CCK-8S (1 ng) decreases morphine analgesia in LPS-treated rats, but not in naïve rats. Consistent with Fukazawa et al (2007), naïve rats (non-LPS rats) do not show a decrease of morphine sensitivity with this dose of CCK-8S. This suggests that LPS-treated rats show increased responsiveness to the anti-opioid effects i.t.…”

Differences in Neural-Immune Gene Expression Response in Rat Spinal Dorsal Horn Correlates with Variations in Electroacupuncture Analgesia

“…On the other hand, the expression of Cck was significantly increased after 2 Hz EA stimulation and not different between HR and NR in DH. This result that Cck mRNA level was increased after EA and there was no difference between HR and NR was consistent with the previous studies in DH and supraspinal regions [6], [10], [46], while the Cck protein level was higher in NR than HR in the midbrain periaqueductal gray and the perfusate of the rat spinal cord [6], [16]. The mRNA level of the Cck-a receptor in DH had no significant difference in NR and HR of this study, which was inconsistent with one previous study in hypothalamus that Cck-a mRNA level was high expressed in NR than HR [8].…”

Polyanalgesic Consensus Conference 2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel

“…Preclinical data on IT opioids published between January 15, 2007, and March 1, 2011, are summarized in Table 9(14,15,56–80).…”