Spinal Neuronal NOS Signaling Contributes to Morphine Cardioprotection in Ischemia Reperfusion Injury in Rats

Abstract

Morphine has been widely used as rescue treatment for heart attack and failure in humans for many decades. Relatively little has been known about the role of spinal opioid receptors in morphine cardioprotection. Recent studies have shown that intrathecal injection of morphine can reduce the heart injury caused by ischemia (I)/reperfusion (R) in rats. However, the molecular and cellular mechanisms underlying intrathecal morphine cardioprotection has not been determined. Here, we report that intrathecal morphine postconditioning (IMPOC) rescued mean artery pressure (MAP) and reduced myocardial injury in I/R. Pretreatment with either naloxone (NAL), a selective muopioid receptor antagonist, or nitric oxide synthase (NOS) inhibitors via intrathecal delivery completely abolished IMPOC cardioprotection, suggesting that the spinal mu-opioid receptor and its downstream NOS signaling pathway are involved in the mechanism of the morphine-induced effect. Consistent with this, IMPOC significantly enhanced spinal neural NOS phosphorylation, nitric oxide, and cGMP content in a similar time course. Intrathecal application of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific inhibitor of guanylate cyclase, completely ablated IMPOC-induced enhancement of cardioprotection and spinal cGMP content. IMPOC rescue of MAP and ischemic injury is correlated with IMPOC enhancement of NOS signaling. Collectively, these findings strengthen the concept of spinal mu-opioid receptors as a therapeutic target that mediates morphine-induced cardioprotection. We also provide evidence suggesting that the activation of spinal NOS signaling is essential for morphine cardioprotection.

Intrathecal lentivirus-mediated RNA interference targeting nerve growth factor attenuates myocardial ischaemia–reperfusion injury in rat

“…In previous studies, we have established the method of intrathecal injection and delivered drugs such as opioids to limit cardiac injury, demonstrating an important role of spinal neural signalling in cardioprotection. 16,29,30 Our work confirms that now intrathecal application of shRNA is a useful approach for elucidating gene function in pain and nociceptive signalling. 31e33 It may be possible to administer small molecules targeting NGF or TRPV1 locally in the spinal cord before surgery to prevent perioperative myocardial injury.…”

“…Intrathecal catheterisation at the T2eT6 level of the thoracic spinal cord was performed as described previously. 15,16 After recovery for 3 days, the animals received a single injection with NGF-shRNA, NC-shRNA or normal saline in the same volume (10 ml) via the implanted catheter, followed by additional 10 ml saline infusion. The dead space of the catheter lumen was approximately 10 ml.…”

Identification of lncRNA and mRNA expression profiles in rat spinal cords at various time‑points following cardiac ischemia/reperfusion

“…of neurons in the intermediolateral nucleus of the spinal cord and the rostral ventrolateral medulla of the brainstem via the sympathetic pathway (12). The spinal cord has been implicated in the pathogenesis of cardiac injury caused by I/R (4,(13)(14)(15)(16). Furthermore, there is convincing evidence that the heart receives dense innervation from sensory afferent fibers, which peripherally release a variety of vasodilator neuropeptides, such as calcitonin gene-related peptide (CGRP) (17) and substance P (SP), in response to local stimuli (18).…”

The effect of intrathecal sufentanil preconditioning against myocardial ischemia-reperfusion injury

“…Central receptors play an important role at the beginning of the procedure, and peripheral receptors have a role in the continuation of this effect (16). The recent study also emphasized that spinal mu-opioid receptors and the activation of nitric oxide synthase (NOS) signaling were involved in the cardioprotective effects of IT morphine (17).…”