Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition

Abstract

Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and anti-inflammatory effects of non-opioids. The present review will discuss the multiple actions of non-opioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects.

Keywords: NSAIDs; cholinergic system; endocannabinoids; inflammatory pain; interleukin-6; matrix metalloproteinases; monoaminergic systems; nitric oxide.

Fig 1

A hypothetical diagram of possible sites of interaction between non-opioids and the endocannabinoid system. Endocannabinoids including anandamide are proposed to be released from the post-synaptic neurons upon depolarization, diffuse or actively transported via AMT (anandamide membrane transporter) to the presynaptic neuron and activate cannabinoid CB₁-receptors. AMT, which is activated by nitric oxide (NO), is also responsible for the cellular uptake of AEA where it is hydrolyzed by either FAAH (fatty acid amidohydrolase) into arachidonic acid (AA) and ethanolamine, or by cyclooxygenase 2 (COX2) into PGE₂ ethanolamide. Non opioids are known to inhibit COX2 and some of them can inhibit FAAH. Non-opioids also modulate NO synthesis and AMT might be inhibited by acetaminophen. Finally, inhibition of COX might result in a shift of AA metabolism towards the synthesis of endocannabinoids.

Fig 2

A hypothetical diagram of possible sites of action of non-opioids in the regulatory pathway of IL-6. IL-6 binds to IL-6 receptor forming a hexadimer with intracellular gp-130 molecule. This activates (phosphorylates) JAK-1 (Janus kinase 1), which leads to the phosphorylation of gp-130 and subsequently the activation of STAT1 and STAT 3 (signal transducers and activators of transcription). The activation of this signaling cascade results in the induction of SOCS3 formation that ultimately inhibits the signaling transduction of IL-6. PGE₂ via EP₂ and EP₄ receptors activates adenylyl cyclase leading to the formation of cAMP that activates (protein kinase A) PKA and subsequently NFkB (nuclear factor kappa B). NFκB activation results in further IL-6 expression and it also interferes with activation of STAT. Non-opioids interfere with synthesis of PGE₂, the degradation of c-AMP and also regulates SOCS 3and NFκB. It should be noted that non-opioids have different effects on these targets in different cells and under different experimental conditions.

Fig 3

A hypothetical diagram of possible sites of action of non-opioids in the regulatory pathway of MMPs. TNF-α and IL-1 activates the MAPKs ERK1/2, p38, and JNK, which results in phosphorylation of the components of AP-1, and the upregulation of MMPs. Activation of MAPKs also may result in upregulation of secondary mediators such as, IL-6 or PGE₂. IL-6 via the JAK/STAT pathway may upregulate MMPs. PGE₂ via EP₄ receptors activates adenylyl cyclase leading to the formation of cAMP that interfere with the activation of ERK. NFκB is also involved in the regulation of MMPs expression. Non-opioids interfere with synthesis of PGE₂, the degradation of c-AMP and also regulate various cytokines. They regulate AP-1, NFκB and MAPKs. It should be noted that non-opioids have different effects on these targets in different cells and under different experimental conditions

Fig 4

A hypothetical diagram of possible regulatory mechanisms of non-opioids on MMPs. It should be noted that non-opioids have different effects on these targets in different cells and under different experimental conditions. Abbreviations: NO, nitric oxide; IL-6, Interleukin-6; MCP-1, Monocyte Chemoat-tractant Protein-1; MMPs, matrix metalloproteinases; SOCS3, suppressor of cytokine signaling 3; IL-8, Interleukin-8; IL-1, Interleukin-1; PGE₂, prostaglandin E₂; TIMPs, tissue inhibitors of metalloproteinases; t-PA, tissue plasminogen activator; u-PA, urokinase; TNFα, tumor necrosis factor α.

Fig 5

Possible targets that contribute to the analgesic effects, anti-inflammatory action or adverse effects of non-opioids in the central nervous system, the peripheral sites of inflammation or the blood vessels.