Access to the PPM Journal and newsletters is FREE for clinicians.
10 Articles in Volume 16, Issue #5
A Review of Skeletal Muscle Relaxants for Pain Management
Applying Kinesiology as a Multi-Prong Approach to Pain Management
Arachnoiditis: Diagnosis and Treatment
Bench to Bedside: Clinical Tips from APS Poster Presentations
Conversation With David Williams, PhD, President of the American Pain Society
Letters to the Editor: Prince Fentanyl Overdose, High-Dose Opioids, Mystery Care
Los Angeles Times Versus Purdue Pharma: Is 12-Hour Dosing of OxyContin Appropriate?
My Experience With OxyContin 12-Hour Dosing
Technology: Changing the Delivery of Healthcare
The Neuroscience of Pain

The Neuroscience of Pain

A primer on the neurobiology of pain pathways.


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.

There is a significant amount of evidence that suggests that the ACC is involved in the processing of pain. A previous review revealed that neural activity present in the ACC increases due to noxious stimuli, but it does not alter response to non-noxious stimuli.8 In addition, the use of hypnotic suggestions before and during the application of a noxious stimulus changed the regional cerebral blood flow in the ACC. However, these changes were not observed in the somatosensory cortex, leading to a conclusion that the ACC is involved in the processing of pain, but not in the sensory processing of  noxious stimuli.8

The application of endogenous opioid signaling in the ACC contributes to the modulation of pain and seems to be required for the relief of pain as well as the downstream activation of dopamine signaling.8 In addition, in a study investigating individuals with low back pain, pain behavior was correlated with high levels of activity in the right insular cortex and pregenual anterior cingulate in response to innocuous cues, which may contribute to the constant occurrence of chronic pain behavior.9 The insular cortex, in particular, often is activated during noxious stimulation and has been suggested to play an important role in pain processing.

Studies also provide evidence that the insula cortex receives afferent nociceptive information, transmitted from second somatosensory cortex to the posterior insula, and then to the anterior insula.10 In addition, connections of the insula with the prefrontal cortex, ACC, and amygdala can allow painful information to be integrated with information related to working memory, affect, and attention.10

The connectivity of the insula to other areas of the brain may play a complex and multifaceted role in the modulation of pain because it can be involved in pro-nociceptive and anti-nociceptive processes. Activity in the anterior insula also can modulate activation of the prefrontal cortex and ACC in a task- or situation-dependent manner, which indicates that the insula can use cognitive information to regulate areas of the brain involved in processing of sensory-discriminative, affective, and cognitive-evaluative aspects of pain.11  Damage to the insula would result in increased pain sensitivity, considering its role in modulating various aspects of nociceptive processing.11

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

Join The Conversation

Register or Log-in to Join the Conversation
close X