Spinal α₂‐adrenoceptors and neuropathic pain modulation; therapeutic target

Abstract

Neuropathic pain can arise from disease or damage to the nervous system. The most common symptoms of neuropathic pain include spontaneous pain, allodynia, and hyperalgesia. There is still limited knowledge about the factors that initiate and maintain neuropathic pain. However, ample evidence has proved the antinociceptive role of spinal α‐adrenoceptors following nerve injury. It is well‐documented that https://www.sciencedirect.com/topics/neuroscience/norepinephrine descending pathways from supraspinal loci exert an inhibitory influence on the spinal cord nociceptive neurons, mostly through the activation of spinal α2‐adrenoceptors. This, in turn, suppresses transmission of pain input and the hyperexcitability of spinal dorsal horn neurons. There is considerable evidence demonstrating that spinal application of α2‐adrenoceptor https://www.sciencedirect.com/topics/neuroscience/agonists leads to analgesic effects in animal models of neuropathic pain. Today, despite the recent rapid development of neuroscience and drug discovery, effective drugs with clear basic mechanisms have remained a mystery. Here, we give an overview of the cellular mechanisms through which brainstem adrenergic descending inhibitory processing can alter spinal pain transmission to the higher centres, and how these pathways change in neuropathic pain conditions focusing on the role of spinal α2‐adrenoceptors in the spinal dorsal horn. We then suggest that α2‐adrenoceptor agonist may be useful to treat neuropathic pain. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

Role of Spinal Cord α2-Adrenoreceptors in Noradrenergic Inhibition of Nociceptive Transmission During Chemotherapy-Induced Peripheral Neuropathy

“…We have recently shown that in paclitaxel-induced CIPN there is an increased activation of serotoninergic RVM neurons (Costa-Pereira et al, 2019). Since the RVM targets the LC and this connection is relevant for descending noradrenergic pain modulation (Sim and Joseph, 1992;Bahari and Meftahi, 2019) it is possible that the activation of RVM neurons recently reported in the paclitaxel-induced CIPN model (Costa-Pereira et al, 2019) is a trigger of increased recruitment of noradrenergic descending modulation during CIPN.…”

Crocin suppressed cold allodynia and anxiety through ?2-adrenoceptors in the anterior cingulate cortex following chronic constriction injury of sciatic nerve in rats

“…So, to the best of our knowledge, this is the first time that such study investigates the mechanism of anti-nociceptive effects of crocin. It is well documented that αadrenoceptors are an important therapeutic target for pain [5]. In the spinal cord level, descending adrenergic projection from the brain stem nuclei to the spinal cord can suppress pain perception [34].…”

“…The underlying mechanism of neuropathic pain is far from clear. The α-adrenoceptors have critical contribution in the process of pain information [5]. Nakai and colleagues revealed that intrathecal injection of guanfacine (an α2Aadrenoceptors agonist) and nitrobiphenyline (an α2C-adrenoceptor agonist) increased mechanical thresholds in a rat model of trigeminal neuropathic pain [6].…”

<p>Role of Melatonin in the Regulation of Pain</p>

“…130 Moreover, activation of the noradrenergic descending pathway inhibits the activities of the spinal cord nociceptive receptors, such as α 2 -adrenoceptors. 131,132 It is documented that intrathecal melatonin alleviates mechanical allodynia response in the formalin test, which is mediated through α 1 -adrenoceptors, α 2 -adrenoceptors, muscarinic, and nicotinic receptors in the spinal cord. 60 In addition, agomelatine exhibits anti-allodynia through noradrenergic neurotransmission mediated by α 2 -adrenoceptors and β 2 -adrenoceptors.…”