Neuroimmune Interactions of Pain

Figure 1
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Activation of a microglia cell can occur in multiple ways.
This activation results in the release of many proinflammatory molecules.
Image source: Watkins and Maier (2002)

Pain is a product of various pathways and mechanisms within the nervous system in response to inflammation or trauma. Within the last couple of decades, more research has shown the important roles the immune system plays in the maintenance and modulation of pain. Many different types of immune cells and glial cells, such as microglia and astrocytes, play key roles in the pain response by releasing various molecules into their surrounding environment [1]. Microglial cells can release proinflammatory cytokines which act on surrounding neurons, triggering a intracellular cascade leading to hyperexcitability of these neurons. This hyperexcitability causes a more intense and longer sensation of pain [1]. Some immune cells also contain opioid peptides which can be released to reduce the sensation of pain by acting on opioid receptors on sensory neurons [2]. Continued research into the neuroimmune interactions of pain will help increase our understandings of pain and could potentially lead to new treatments.

1. Glial and Immune Cells

Until recent research from the past few decades, pain was believed to be the product of interactions only between neurons. This theory was not entirely correct as it left out the crucial importance of other cells involved in the transmission and sensation of pain. These additional cells are those of the immune system or ones that are immune-related. Two of the most heavily researched of these cells that have been implicated in the pain process are microglia and astrocytes which are found throughout the CNS and PNS. They are capable of releasing immune substances such as excitatory amino acids (EAA), postglandins, nitric oxide (NO) and proinflammatory cytokines (PICs)[3]. Glial cells are typically in a resting state where they are participating in homeostatic processes of their environment, but can be activated in response to some forms of stimulation [4].

2. Activation of Glial and Immune cells

2.1. Microglia

Microglia and astrocytes are activated at different slightly different times in response to a change in the environment. This is because they carry out different tasks in the pathway of pain [5]. Inflammation or trauma is first detected in the peripheral nervous system, this can cause the synthesis of proinflammatory mediated molecules (PMMs) which are released in the dorsal horn of the spinal cord. Afferent neurons then release molecules such as substance P and Fracktalkine which act on microglia cells to activate them [1]. In a rat model study, researchers were able to track mRNA expression of microglial proteins TLR4, MAC-1 and CD14. The up regulation of these proteins was found to be very fast following a nerve injury [5]. This study suggested that microglia act as the first responders to the site of injury by releasing proinflammatory mediated molecules. These results were confirmed in another study where a microglia inhibitor known as minocycline was found to prevent the immediate onset of enhanced pain in an affected area [6].

2.2. Astrocytes

Astrocytes are activated in response to infection, inflammation or trauma [7]. This activation can be measured by the up regulation of the expression of GFAP (glial fibrillary acidic protein) in astrocytes. This up regulation has been found in rats following nerve injury, indicating that astrocytes are playing a role in a pain response [8]. Astrocytes typically activate later than microglia [5]. Astrocytes help with the prolonged state of pain following an injury by maintaining the pain state through the continued release of relevant pro-inflammatory molecules [5]. This longer pain state is an adaptive component of pain as it protects the affected area and allows for it to heal [1]. Thus, microglia provide the initial response to trauma, inflammation or infection followed by the prolonged actions of astrocytes.

3. Pro-inflammatory Cytokines (PICs)

Following activation from inflammation or trauma, glial cells release a number of different molecules that play a role in the sensation of pain. One of these types of molecules are proinflammatory cytokines. In a study, researchers analyzed cerebrospinal fluid (CSF) from individuals who suffer from chronic pain disorders. When compared to healthy adults, the chronic pain patients’ CSF contained altered levels of inflammatory cytokines. The chronic pain patients had elevated levels of IL-1β (pro-inflammatory cytokine) and decreased levels of IL-10 (anti-inflammaotry cytokine). This indicates that cytokines appear to play some role in pain [9].

3.1. Hyperexcitability

One of the main effects of these proinflammatory cytokines is their ability to enhance pain through increasing neuronal excitability. In a rat model study, the pro-inflammatory cytokine IL-1β was injected into spine of rats. The results showed an increase in allodynia (pain to typically painless stimuli) and hyperalgesia (extreme pain sensitivity) [10]. Through a molecular cascade, these proinflammatory cytokines are capable of inducing hyperexcitability of sensory neurons [1]. This hyperexcitability enhances the pain state at the affected region.

4. Immune-derived Opioids

In contrast to the hyperexcitability of neurons and the enhancement of pain, there are also immune mechanisms involved in the reduction (analgesia) or control of pain. This process is facilitated by the release of opioids released from immune cells which then act on sensory neurons to reduce the pain state [2].

4.1. Release of Opioid Peptides from Immune Cells

In a type of immune cell called a leukocyte, a precursor protein to opioid peptides known as POMC is present [11]. Following inflammation to an area, these leukocytes must maneuver themselves to that affected region. This migration occurs through the signaling of many molecules that are being released by immune and endothelial cells of the affected area; these include chemokines, CXCL1 and CXCL2/3 [11]. These chemokines than up-regulate adhesion molecules such as α4 and β2 integrins and ICAM-1 [11]. With the help of these adhesion molecules, leukocytes are able to move through the endothelium to their destination. Within the inflamed environment there are many pro-inflammatory molecules present, three of these are CRF, noradrenaline and IL-1β. These three molecules can then bind to corresponding receptors on the leukocytes and trigger the release of opioids into the surrounding environment [2].

Figure 2.
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The migration of leukocytes to a site of inflammation where they will release opioid peptides.
Image source: Hua, S. & Cabot P.J. (2010)

4.2. Opioid Receptors on Sensory Nerves

There are three different types of opioid receptors: μ, 𝛿 an 𝑘. All of these are expressed on sensory neurons [13]. They can be located on peripheral terminals of afferent sensory neurons and on cell bodies of dorsal root ganglia [13]. Synthesis of these opioid receptors occurs within the dorsal root ganglia [14]. The movement of these receptors to peripheral sensory nerves occurs following inflammation of an area. This has been shown in rat models where opioid receptors are increased on cutaneous nerves following induced inflammation of tissue in a rat’s paw [15]. A study using a similar design, showed that opioid receptors are transported via axonal transport from the cell body to the the peripheral nerve terminal following inflammation to the rat paw [16].

4.3. Reduction in Pain

As opioid peptides are being released from leukocytes in an affected environment, the opioid receptors are also unregulated on peripheral nerves. The opioid peptides can then bind to these receptors and initiate actions that reduce the pain sensation. Opioids then block the release of proinflammatory cytokines which consequently reduces the sensation of pain (anglesia) [17].

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