Transition from Acute to Persistent Pain

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Neural plasticity, "the capacity of neurons to change their function, chemical profile, or structure," is the basis for learning and memory and is also responsible for alterations in noxious perception. More so, neural plasticity underlies peripheral and central sensitization. The sensitization theory of pain perception suggests that brief high-intensity noxious stimulation in the absence of tissue injury activates the nociceptive endings of unmyelinated or thinly myelinated (high-threshold) fibers, resulting in physiologic pain perception of short duration. Other low-threshold sensory modalities (pressure, vibration, touch) are carried by larger-caliber (low-threshold) fibers. Large and small fibers make contact with second-order neurons in the dorsal horn (Woolf and Mannion 1999).

Following tissue injuries and release of noxious mediators, peripheral nociceptors become sensitized and fire repeatedly. Peripheral sensitization occurs in the presence of inflammatory mediators, which in turn increases the sensitivity of high-threshold nociceptors as well as the peripheral terminals of other sensory neurons. This increase in nociceptor sensitivity, lowering of the pain threshold, and exaggerated response to painful and non-painful stimuli is termed primary hyperalgesia.

The ongoing barrage of noxious impulses sensitizes second-order transmission neurons in the dorsal horn via a process termed windup. This creates several problems, including sprouting of Wide Dynamic Range (WDR) neurons and induction of glutamate-dependent N-methyl-D-aspartate (NMDA) receptors.

The NMDA receptor is an important four-subunit, voltage-gated, ligand-specific ion channel. Glutamate is the primary agonist of the NMDA receptor and therefore, the primary excitatory agonist for noxious transmission. Glutamate binding to NMDA receptors sustains an inward Ca2+ flux. Second messengers are then upregulated, which slowly prime and maintain excitability of these NMDA receptors. These changes increase neuronal excitability and underlie subsequent plasticity. The NMDA receptor appears to be responsible for not only amplifying pain, but also causing opioid tolerance.

As pain signals continue to enter the dorsal horn and synapse with the nerve cell bodies, WDR neurons can be found in areas of the dorsal horn, where they were not previously located. Specifically, they grow into the areas where pain-receiving nerve cell bodies are located. WDR neurons can experience a broad range of stimulating signals and pass these on to the brain or spinal cord. Once C-nociceptive fibers are activated and continue to overwhelm the nerve cells in the dorsal horn, A| touch sensitive fibers begin to fire and this affects nerve cell bodies in the DRG and the dorsal horn. Glutamate, an extremely fast neurotransmitter, is released at the DRG presynaptic membrane and attaches to non-NMDA nerve cell receptors in the dorsal horn. After continued bombardment by C fibers and A| fibers the magnesium ion, which normally prevents NMDA post-synaptic receptors from receiving glutamate, is displaced and a process known as "windup" begins. Due to ongoing pain signals reaching and being amplified at the dorsal horn, the nerve cells begin to increase the number of NMDA receptors at the post-synaptic membrane. This further increases windup and exhibits increased tolerance to opioids.

"Windup" is a term used to describe the process of increased central sensitization of the body's pain pathways in response to sustained input from nociceptive afferents. Central sensitization results in secondary hyperalgesia and the spread of the hyperalgesic area to nearby uninjured tissues. Inhibitory interneurons and descending inhibitory fibers modulate and suppress spinal sensitization, whereas analgesic under medication and poorly controlled pain favors sensitization. In certain settings, central sensitization may then lead to neuro-chemical/neuroanatomical changes (plasticity), prolonged neuronal discharge and sensitivity (windup), and the development of chronic pain. Activation of spinal and supraspinal NMDA receptors and increased Ca2+ ion influx are major requisites for the development of central sensitization. It is the sensitization of CNS neurons that underlies the transition from acute to persistent pain. Excitatory neurotransmitters are believed to cause spinal cord hypersensitivity to nociceptive inputs from the periphery. Excitotoxicity defines the pathological alterations observed in nerve cells stimulated by overactivation of NMDA.

There are certain mediators responsible for central sensitization and associated plasticity changes. Inflow of Ca2+ ions initiates the upregulation of COX-2, nitric oxide systems (NOS), and second messengers that initiate transcriptional and translational changes. Central sensitization can be divided into transcription-dependent and transcription-independent processes. Transcription-independent sensitization reflects neurochemical and electrical alterations that follow acute traumatic injury. It includes stimulus-dependent neuronal depolarization and stimulus-independent long-term potentiation. Windup is a form of transcription-independent central sensitization (Woolf 1983).

Transcription-dependent sensitization describes delayed-onset, long-lasting, noxious facilitation that follows genomic activation, transcription of messenger RNA (mRNA), and subsequent translational modifications. Following transcription of mRNA, inducible enzymes and reactive proteins are synthesized that mediate neuroanatomical and neu-ropathologic plasticity (Ji and Woolf 2001).

Opioid-induced hyperalgesia is a process that is associated with the long-term use of opioids for pain management. Opioid-induced hyperalgesia is a clinical picture which is characterized by increasing pain in patients who are receiving increasing doses of opioids. With time, individuals using opioids can develop an increasing sensitivity to noxious stimuli, sometimes even staging a painful response to non-noxious stimuli. Therefore, patients given opioids for acute pain may have a paradoxical increase in pain. Opioid-induced hyperalgesia is a result of glutamate-associated activation that occurs at the level of the NMDA receptor in the dorsal horn of the spinal cord. There is evidence that NMDA antagonists, such as ketamine, have a role in preventing opioid-induced hyperalgesia.

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