Physiopathological Bases of Pain and Inflammation

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The Arachidonic Acid Cascade and Cyclooxygenases

Tissue aggression stimulates membrane phospholipases (such as PLA₂), releasing arachidonic acid. This lipid serves as a substrate for the cyclooxygenase pathway, producing prostaglandins, prostacyclin and thromboxane:

🔄 Cyclooxygenase-1 (COX-1)

Constitutively expressed in practically all body tissues. It performs basic homeostatic maintenance functions:

• Gastric cytoprotection: Synthesis of PGE₂ and PGI₂, which stimulate the secretion of mucus and bicarbonate and maintain mucosal blood flow.
• Platelet homeostasis: Production of Thromboxane TXA₂, a powerful platelet aggregator and vasoconstrictor.
• Renal perfusion: Preservation of glomerular filtration under conditions of systemic vasoconstriction.

🔥 Cyclooxygenase-2 (COX-2)

Highly inducible by proinflammatory cytokines (IL-1, TNF-α), lipopolysaccharides and growth factors at the site of tissue injury:

• Inflammatory signaling: Massive synthesis of PGE₂, which promotes vasodilation, chemotaxis and increased capillary permeability.
• Peripheral sensitization: Decrease in the activation threshold of primary afferent nociceptors.
• Central systems: Inducible in the CNS (hypothalamus), mediating fever and central hyperalgesia.

Mechanism of Nociception and Opioid Modulation

The transmission of the painful stimulus travels through fast myelinated Aδ fibers and slow unmyelinated C fibers. These primary afferent neurons synapse in the dorsal horns of the spinal cord (laminae of Rexed I and II), using glutamate and substance P as neurotransmitters.

Opioid Receptor Signaling

Opioid receptors (µ, κ, δ) belong to the family of G protein-coupled receptors of the G_i/G_o type. Its molecular activation causes the following dual effect:

1. Presynaptic Effect: Direct inhibition of N-type voltage-gated calcium channels. By preventing the entry of calcium (Ca²⁺), the exocytosis and release of neurotransmitter vesicles containing glutamate, substance P and calcitonin gene-related peptide (CGRP) are blocked.
2. Postsynaptic Effect: Coupled opening of internally rectifying potassium channels activated by G proteins (GIRK). The massive outflow of potassium (K⁺) hyperpolarizes the postsynaptic membrane, reducing the probability of generating an action potential and propagating the pain signal through the spinothalamic pathway.

The Transition to Rheumatic Chronicity

In autoimmune pathologies such as rheumatoid arthritis, the target shifts from acute nociception to the control of chronic synovitis. The infiltration of CD4+ T lymphocytes, macrophages and dendritic cells into the synovial tissue perpetuates the release of effector cytokines. Selective blockade of mediators such as tumor necrosis factor alpha (TNF-α), or interference with the Janus kinase pathway (JAK-STAT), stops the transcriptional cascade that promotes angiogenesis, osteoclast recruitment, and matrix metalloproteinase (MMP)-mediated cartilage destruction.