Pain Points of View

The Biochemistry of Pain

Inflammation causes the release of numerous chemicals that may alter the sensitivity of peripheral nerve terminals.¹Wall & Melzack. Textbook of Pain, 5th Edition. 2006. p16 Chemical messengers that convey pain information to the CNS via the spinal cord can also affect the sensitivity of dorsal horn neurons.²Ossipov MH. The Perception and Endogenous Modulation of Pain.2012. p6.

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.³Wall & Melzack.Textbook of Pain, 5th Edition. 2006. p16

Glutamate

Glutamate is the predominant primary afferent neurotransmitter, eliciting fast excitatory responses in postsynaptic neurons in the dorsal horn of the spinal cord.⁴Wall & Melzack. Textbook of Pain, 5th Edition. 2006. p36

ATP

ATP enhances glutamate release during firing of presynaptic autoreceptors and depolarization of postsynaptic dorsal horn receptors.⁵Wall & Melzack Textbook of Pain, 5th Edition. 2006. p36.

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.⁶Wall & Melzack. Textbook of Pain, 5th Edition. p36

Bradykinin

Bradykinin may play a critical role in inflammatory pain and hyperalgesia by acting directly on sensory nerves and by indirectly evoking the release of other inflammatory mediators from non-neuronal cells.⁷Wall & Melzack. Textbook of Pain, 5th Edition. p51.

Serotonin

Serotonin can intensify pain induced by bradykinin and enhance the response of nociceptors to bradykinin.⁸Wall & Melzack. Textbook of Pain, 5th Edition. p17

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.⁹Mizumura K, Murase S. Role of Nerve Growth Factor in Pain. In: Schaible HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer. 2015. p58.

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 (see Sect. 7.1). 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.¹⁰ Mizumura K, Murase S. Role of Nerve Growth Factor in Pain. In: Schaible HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer. 2015. p59

NGF also facilitates the heat response of muscle C-fibers.¹¹Mizumura K, Murase S. Role of Nerve Growth Factor in Pain. In: Schaible HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer. 2015. p64

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).¹²Mizumura K, Murase S. Role of Nerve Growth Factor in Pain. In: Schaible HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer. 2015. p66.

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.¹³Mizumura K, Murase S. Role of Nerve Growth Factor in Pain. In: Schaible HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer. 2015. p66.

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.¹⁴Stratiievska A et al. Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor. Elife. Dec 2018. p1. 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.¹⁵Stratiievska A et al. Reciprocal regulation among TRPV1 channels and phosphoinositide 3-kinase in response to nerve growth factor. Elife. Dec 2018. p2