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 noradrenergic 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 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.

Figure 1

Brainstem inhibitory descending adrenergic modulation of pain in the physiological and the chronic neuropathic pain conditions. (a) Brainstem adrenergic inhibitory modulation of nociception in physiological condition. Application of noxious stimuli induces transmission of nociceptive information from ascending pathways to higher centres. At this time, noxious stimuli activate a brainstem adrenergic inhibitory pathways and increased the release of NA in dorsal horn from descending terminals. Activation of α₂‐heteroreceptors on the presynaptic cell decreased entry of Ca²⁺ to cell and subsequently suppresses the release of glutamate and other stimulatory neurotransmitters via Gi‐protein activity. Additionally, the activity of α₂‐heteroreceptors on the postsynaptic cell increased efflux of K⁺ from the cell and subsequently shift membrane potentials to a negative voltage via Gs‐protein activity. (b) Neuroplasticity changes in the brainstem descending adrenergic circuitries and the spinal cord in chronic neuropathic pain states. After nerve injury, up‐regulation of P2X4 receptors increased the release of BDNF from glial cells. The release of BDNF can induce descending adrenergic fibre sprouting and enhances analgesia effects of α₂‐heteroreceptor agonists in chronic neuropathic pain. (c) Analgesic spinal effects of α₂‐adrenoceptor (AR) agonist in chronic neuropathic pain. Although application of α₂‐adrenoceptor agonist can induce analgesic effects via heteroreceptors on the pre and postsynaptic cells. However, in pharmacological studies α₂‐adrenoceptor agonists can also decrease NA release from brainstem descending adrenergic terminals via autoreceptors and Gi‐protein activity in chronic neuropathic pain

Figure 2

Cellular mechanisms for analgesic effects of α₂‐adrenoceptor (AR) agonists; α₂‐adrenoceptors located both in the peripheral sensory neurons and spinal neurons. The activation of α₂‐adrenoceptors on presynaptic cells, using an α₂‐adrenoceptor agonist, reduces the activity of AC, suppressing both the production of the cAMP and the activity of PKA. Then, suppressing the activity of PKA inhibited the presynaptic N‐type voltage‐gated Ca²⁺ channels (1) and TRPV1 channel activity (2); subsequently, the influx of Ca²⁺ ions to presynaptic cell and the release of stimulators neurotransmitters such as glutamate, substance P, and CGRP from primary fibre terminals in the spinal cord are decreased (3). Furthermore, application of α₂‐adrenoceptor agonist increases the activity of Gs proteins in the postsynaptic cells. Activation of Gs protein, increased both the production of the cAMP and the activity of PKA, and then the activity of K⁺ _ir channels and efflux of K⁺ ions are increased. Efflux of K⁺ ions induced hyperpolarization in the postsynaptic neurons (4). Nerve injury increased the release of ATP from the peripheral sensory neuron and also induced an up‐regulation of P2X4 receptors on glial cells (5). The activity of P2X4 receptors increased the release of BDNF from glial cells (6). At the same time, activation TrkB receptors on cholinergic interneurons (7) and its interaction with α₂‐adrenoceptors via unknown mechanisms elicited the release of ACh (8). Activation of muscarinic receptors directly on the postsynaptic cells (9) or indirectly on the inhibitory GABAergic or glycinergic interneurons (10) can also induce hyperpolarization in the postsynaptic cells (11). Therefore, the application of an α₂‐adrenoceptor agonist elicited hyperpolarization in the postsynaptic cell via above‐mentioned mechanisms. Hyperpolarization of the neuron decreased transmission of pain inputs to higher centres (12) and suppressed pain perception (13)