The Dynamics of Pain: How Neurotransmitters, Immune Cells, and Genetic Factors Shape Pain Experiences and Treatment

 

Pain is the unpleasant sensation a person feels as he or she experiences a sting, burn, or ache caused by the nervous system which might be for short or long duration depending on the intensity. It serves as a symptom, warning the organism that something is wrong with his or her system. It can be experienced both physically and emotionally. 
Researchers have been studying the working of neurotransmitters, nociceptors ( pain causing cells) and other molecules in the brain or spinal cord that cause pain, resulting in better understanding about pain. They have concluded there are two types of chronic pain, neuropathic pain, that directly affects the nerve and inflammatory/nociceptive pain, that is caused due to tissue damage and inflammation leading to the damage of nerve fibers. These damages in the nerve fibers lead to the changes in dorsal root ganglions, which include hormonal changes, increased nerve cell activity, altered immune signals in the central nervous system. 

Perkins and Tracey removed neutrophils from the injured person’s blood and noticed no neuropathic pain in the person, since the neutrophils move to the damaged nerve, hence proving Zuo et al’s observation that partial sciatic nerve injury triggered the  activation of the immune system. This worked only when it was removed immediately after injury. Similarly, removal of macrophages and T-cells resulted in no heat sensitivity pain. Blood-derived leukocytes and resident microglia were also noticed in the spinal cord after injury. Microglia which start the development of pain and astrocytes help in maintaining the pain can be treated using fluorocitrate. While minocycline is specific for inhibiting microglia. 

Cytokines like TNFα, IL-1 and IL-6 play a key role in the pain sensation. Mendel.L discovered that nerve growth factor increases neuropathic pain due to the activation of mast cells. NGF also affects the expression of genes that cause pain, leading to the increase in long-term pain sensitivity. McMahon discovered that damaged nerves trigger the release of immune cells which increase the growth factors resulting in unusual signals in both damaged and healthy nerve fibers that end up causing pain.   

Off late, researchers have identified that only some nerve fibers like nociceptors, C fiber and mechanoreceptors, Aẟ induce pain and conduct pain respectively, along with these the myelinated fibers also cause high frequency impulses, that increase the NGF rate, change gene expression and the firing of neurons. The sodium channels are affected differently by different nerve damages, for example axonal nerve damage reduces TTX-resistant sodium channels, which are involved in pain sensitivity and inflammation, while inflammation increases them. 
C-fos expression, an oncogene expression which helps in localisation of sensory and motor neurons of pain, increases during nociceptive stimuli within 30 minutes and wears off after 8 hours in the CNS. cAMP response element-binding protein is also involved in the processing of pain. C fiber remains active for the whole time during chronic inflammation, hence causing synaptic conduction in dorsal root neurons, and in a few minutes can lead to postsynaptic depolarisation. 

Glutamate, substance P, and neurokinin play a key role in transmission of pain signals. The GABA and nitric oxide were also known to be a part of processing pain. Superoxide dismutase activity was also identified as a pain modulator.  More than male, pain was more intense, frequent and prolonged in women, hence suggesting that sexual dysmorphism plays a key role as the sex hormones are different. 

After reviewing all the pain mechanisms, it was concluded that changes in NMDA and AMPA receptors are crucial for pain processing. A part of amygdala has been termed as “nociceptive-amygdala”, because they face neuroplastic, biochemical, pharmacological, and electrophysiological changes during persistent pain.in future, it is believed that one would be able to control pain through gene transfer technologies but only if the molecular biology of genes causing neuronal pain is studied well. 

REFERENCE
Pace MC, Mazzariello L, Passavanti MB, Sansone P, Barbarisi M, Aurilio C. Neurobiology of pain. Journal of cellular physiology. 2006 Oct;209(1):8-12.

IMAGE REFERENCE
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