Subscription is FREE for qualified healthcare professionals in the US.

The Neuroscience of Pain

A primer on the neurobiology of pain pathways.
Page 1 of 2


Two nerves communicating on a microscopic level.

The sensation of pain is a necessary function that warns the body of potential or actual injury. It occurs when a nociceptor fiber detects a painful stimulus on the skin or in an internal organ (peripheral nervous system).1 The detection of that signal is “picked up” by receptors at the dorsal horn of the spinal cord and brainstem and transmitted to various areas of the brain as sensory information.

The facilitators of this pathway are known as neurotransmitters. Neurotransmitters are endogenous chemical messengers that transmit signals across a chemical synapse, from one neuron to another “target” neuron, muscle cell, or gland cell.2 Some neurotransmitters are excitatory, facilitating transmission of messages, while others are inhibitory neurotransmitters, impeding transmission.2 These chemical messages are critical in the modulation of pain.

Activation of an excitatory neurotransmitter receptor results in an electrical message that travels through a neuron to the axon terminal, where the release of neurotransmitters occurs. Excitatory neurotransmitters usually are responsible for providing energy, motivation, mental cognition, and other processes that require brain and body activity.

However, the activation of inhibitory neurotransmitter receptor sites antagonizes the effects of excitatory receptor activation. These neurotransmitters generally are responsible for inducing sleep and filtering out unnecessary excitatory signals. There must be a sufficient amount of neurotransmitters, as well as excitatory and inhibitory systems working in sequence with one another, to stimulate an appropriate response.2 For example, excitatory neurotransmitters acting without an inhibiting system results in pain.1

Nociceptors are specialized sensory receptors responsible for transforming painful stimuli into electrical signals, which travel to the central nervous system via neurotransmitters. Several neurotransmitters are involved in carrying the nociceptive message. However, glutamate and substance P (SP) are the main neurotransmitters associated with the sensation of pain.1

Neurotransmitters: Glutamate and Substance P

Glutamate receptors that are a part of class C G-coupled receptors are known to play a role in several neurological and psychiatric conditions, such as schizophrenia, anxiety, and depression. However, they also play a role in the mechanism of chronic pain, and most of these receptors are found throughout the central and peripheral nervous systems.3

Glutamate transmits pain by binding to 5-subunit ligand-gated ion channels located on nociceptive neurons on myelinated pain afferents belonging to the class of afferent axons known as A-delta that transmit to the dorsal horn of the spinal cord.4 Glutamate is usually involved in the rapid neurotransmission of acute pain, such as with mechanical stimuli or temperature stimuli producing quick, sharp pain.3 In addition, glutamate acts on various types of receptors, including ionotropic receptors that are directly coupled to ion channels, as well metabotropic receptors that are directly attached to intracellular secondary messengers.4

The role of glutamate in the brain is highly complex because activation of glutamate receptors in certain regions of the brain, such as the thalamus and trigeminal nucleus, seem to be pro-nociceptive. However, activation of glutamate receptors in other brain areas, such as the periaqueductal grey and ventrolateral medulla, seems to be anti-nociceptive.5

A ubiquitous neuropeptide, SP is distributed over cytoplasmic and nuclear membranes of many cell types. SP regulates smooth muscle contractility, epithelial ion transport, vascular permeability, and immune function in the gastrointestinal tract. SP transmits pain by secretion from nerves and inflammatory cells, and acts by binding to receptors called neurokinin-1 receptors (NK-1R) that are located on the nociceptive neurons on unmyelinated primary afferents, known as C fibers, to the dorsal horn of the spinal cord.

SP is typically seen in chronic pain cases due to its slow excitatory connection.6 Individuals with a high pain tolerance appear to lack the SP-containing fibers that specifically encode noxious stimuli only in the dorsal horn area.6 The success in treating pain with opiates, such as morphine, that block nociceptive transmission of pain within the spinal cord is perceived to be, in part, due to a decrease in the release of SP.6

Mechanisms of Pain Processing

The mechanism of processing pain is very complex. The dorsal horn is divided into 10 layers called the Rexed laminae. The A-delta and C fibers transmit information primarily to nociceptive-specific neurons located in Rexed laminae I and II. These primary afferent terminals release a number of excitatory neurotransmitters, including glutamate and SP.7

There are 2 main pathways to carry these nociceptive messages to the brain, the spinothalamic and spinoreticular tracts. The spinothalamic tract transmits pain signals that are important to localizing pain. This tract involves afferent neurons that interact with segments of the spinal cord and ascend in the contralateral spinothalamic tract to nuclei within the thalamus.7 These third-order neurons continue the ascending pathway and terminate in the somatosensory cortex and periaqueductal grey matter. The second pathway—the spinoreticular tract—is important in the emotional aspects of pain. The fibers intersect and ascend the contralateral cord to reach the brainstem reticular formation, then the thalamus and hypothalamus and, finally, to make many projections into the cortex.7

Functional magnetic resonance imaging data suggest that a large brain network—including the primary and secondary somatosensory cortex, insular cortex, anterior cingulate cortex (ACC), and prefrontal cortex—is activated during a painful experience.7 However, there are areas within the brain that are more active in the transmission of pain than others.

Last updated on: June 16, 2016
First published on: June 1, 2016
Continue Reading:
Arachnoiditis: Diagnosis and Treatment