The Biochemistry of Pain

Inflammation causes the release of numerous chemicals that may alter the sensitivity of peripheral nerve terminals.⁶¹1 Chemical messengers that convey pain information to the CNS via the spinal cord can also affect the sensitivity of dorsal horn neurons.⁶²2

The biochemical mediators of inflammation

Cytokines and corticotrophin-releasing hormone from inflamed tissue can induce macrophages, monocytes, and lymphocytes to release endogenous opioids that mediate pain.⁶³3

Glutamate

Glutamate is the predominant primary afferent neurotransmitter, eliciting fast excitatory responses in postsynaptic neurons in the dorsal horn of the spinal cord.⁶⁴4

ATP

ATP enhances glutamate release during firing of presynaptic autoreceptors and depolarization of postsynaptic dorsal horn receptors.⁶⁵5

Substance P and CGRP

Substance P and calcitonin gene-related peptide (CGRP) promote vascular leakage and vasodilatation, allowing circulating cells, plasma proteins, and inflammatory mediators to infiltrate the affected area. Substance P interacts with postsynaptic dorsal horn receptors, setting the magnitude of the nociceptive response.⁶⁶6

Bradykinin

Bradykinin may play a critical role in inflammatory pain and hyperalgesiaby acting directly on sensory nerves and by indirectly evoking the release of other inflammatory mediators from non-neuronal cells.⁶⁷7

Serotonin

Serotonin can intensify pain induced by bradykinin and enhance the response of nociceptors to bradykinin.⁶⁸8

Nerve Growth Factor

Nerve growth factor (NGF) plays a role in the development of nociceptive primary neurons. It has also been shown to play a role in inflammatory hyperalgesia in adults. The involvement of NGF in painful conditions with no apparent inflammatory signs has also been demonstrated.⁶⁹9

NGF exerts its activity by binding to a specific receptor, TrkA (receptor tyrosine kinase A, tropomyosin-related kinase A), which is composed of one transmembrane structure, an extracellular domain that binds with NGF, and an intracellular domain with tyrosine kinase activity. When a molecule of NGF binds to TrkA, another molecule of TrkA joins, making a TrkA dimer. Tyrosine kinase is then activated, and information is transmitted intracellularly at the site of binding. In addition, NGF that binds to TrkA is internalized and transported in the axon to the neuronal cell body (signaling endosome), where it changes the expression of neuropeptides, channels, and receptors. Increased neuropeptides, channels, and receptors are then transported both to the central and peripheral terminals, changing their sensitivities.⁷⁰10

NGF also facilitates the heat response of muscle C-fibers.⁷¹11 Upregulation of NGF and its high affinity receptor TrkA was shown in samples obtained from inflammatory bowel disease patients (Crohn’s disease and ulcerative colitis).⁷²12

There are also conditions where no apparent inflammation is the cause of NGF upregulation. Urinary and serum levels of NGF were found to be higher in overactive bladder patients.⁷³13

Transient receptor potential vanilloid subtype 1 (TRPV1) also plays a role in hyperalgesia related to NGF. TRPV1 is a non-selective cation channel that is activated by a variety of noxious stimuli.⁷⁴14 TRPV1 is modulated by G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). As an RTK agonist, NGF is an involved in inflammatory hyperalgesia by acting directly on peptidergic C-fiber nociceptors which express RTK receptors for NGF. In chronic pain, NGF also produces changes in the protein expression of ion channels such as TRPV1. The acute and chronic phases of the NGF response result in increased ‘gain’ to painful stimuli.⁷⁵15