Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats

Abstract

. Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats. J Appl Physiol 98: 2056 -2063, 2005. First published January 13, 2005; doi:10.1152/japplphysiol.01282.2004 at Neiguan-Jianshi acupoints through an opioid mechanism inhibits the cardiovascular pressor response induced by mechanical stimulation of the stomach. Because nociceptin also may regulate cardiovascular activity through its action in the brain stem, we hypothesized that this neuromodulator serves a role in the EA-related inhibitory effect. Blood pressure in ventilated male Sprague-Dawley rats (400 -600 g) anesthetized by ketamine and ␣-chloralose was measured during balloon inflation of the stomach. Gastric distension with 6 -8 ml of air induced consistent pressor reflexes of 26 Ϯ 1 mmHg that could be repeated every 10 min for 100 min. When nociceptin (10 nM) was microinjected into the rostral ventrolateral medulla (rVLM), the pressor response induced by gastric distension was inhibited by 68 Ϯ 6%. Thirty minutes of EA also decreased the reflex response by 75 Ϯ 11%; microinjection of saline into the rVLM did not alter the inhibitory effect of EA. In contrast, microinjection of a nociceptin receptor antagonist into the rVLM promptly reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not influence the EA-like inhibitory effect of nociceptin on the distension-induced pressor reflex (22 Ϯ 1 to 8 Ϯ 2 mmHg). Furthermore, a -opioid receptor agonist microinjected into the rVLM after microinjection of a nociceptin receptor antagonist during EA promptly reversed the nociceptin receptor antagonist-related inhibition of the EA effect. Thus, in addition to the classical opioid system, nociceptin, through opioid receptor-like-1 receptor stimulation in the rVLM, participates in the modulatory influence of EA on reflexinduced increases in blood pressure. opioids; gastric distension; somatic afferent RECENTLY, A NOVEL OPIATE-LIKE heptadecapeptide was identified in rat brain extracts (41,46). The peptide, called nociceptin (41) or Orphanin FQ (46), has a high amino acid sequence homology to classical endogenous opioid peptides (i.e., endorphins, enkephalins, endomorphins, and dynorphins) and especially to dynorphin A. Furthermore, amino acid sequencing of the receptor believed to be specific for nociceptin, or opioid receptor-like-1 (ORL-1), was found to be 47-50% identical to that of the coding sequences of -, ␦-, and -opioid receptors (10,

Medullary GABAergic mechanisms contribute to electroacupuncture modulation of cardiovascular depressor responses during gastric distention in rats

“…We microinjected 50 nl of gabazine, kynurenic acid, or saline unilaterally into the NAmb, rVLM, or cVLM. Of note, several of our previous studies (8,19,42) have demonstrated significant blockade of EA's actions following unilateral administration.…”

“…(8,19,42). In this regard, we have shown that repeated gastric distention induces consistent increases in arterial pressure in normoxic normocapnic rats and that EA modulates these pressor responses (8,12,19,42,48,49). Fewer studies have reported that gastric distention also can reflexly decrease blood pressure (29,39).…”

“…Excitatory and inhibitory neuropeptides in these cardiovascular regions contribute to the inhibition of visceral reflex evoked rVLM neuronal activity during EA (20,27,42,44). In addition to serotonin, nociceptin, endocannabinoids, and opioids (8,21,27,42), GABA, through stimulation of GABA A receptors in the vlPAG and rVLM, participates in the modulating actions of EA (12,42,44).We have demonstrated that EA at P5-P6 acupoints reduces excitatory cardiovascular responses and lowers sustained hypertension by decreasing sympathetic outflow (17,40,42). Although others have suggested that EA at P5-P6 acupoints is able to raise arterial blood pressure when it is low (36, 47), the central neural processing mechanisms underlying this action of EA have not been elucidated.…”

“…Excitatory and inhibitory neuropeptides in these cardiovascular regions contribute to the inhibition of visceral reflex evoked rVLM neuronal activity during EA (20,27,42,44). In addition to serotonin, nociceptin, endocannabinoids, and opioids (8,21,27,42), GABA, through stimulation of GABA A receptors in the vlPAG and rVLM, participates in the modulating actions of EA (12,42,44).…”

The Status and Future of Acupuncture Mechanism Research

“…More recently, we have shown that nociceptin and gamma aminobutyric acid (GABA) are involved in inhibition of visceral reflex-induced increases in blood pressure following 30 minutes of low-frequency EA at P5-P6 acupoints, located over the median nerve on the forearms. 19,20 In our experimental models, we have demonstrated that low-frequency (2-4 Hz) but not high-frequency (20-100 Hz) EA effectively stimulates somatic afferents to provide input to regions such as the rVLM that regulate sympathetic outflow. 15,21 Our studies have also examined the concept of point specificity with regard to acupuncture's ability to lower elevated BP.…”