Pathophysiology+of+Neuropathic+pain

Neuropathic pain — Neuropathic pain arises from abnormal neural activity secondary to disease, injury, or dysfunction of the both pheripheral and central nervous system. It commonly persists without ongoing disease (eg, diabetic neuropathy, causalgia, phantom limbs, postherpetic neuralgia, stroke, spinal cord injury, and multiple sclerosis). 1) Sympathetically mediated pain (SMP) is pain arising from a peripheral nerve lesion and is associated __with autonomic changes__ (Ex: complex regional pain syndrome I and II) 2) Peripheral neuropathic pain is due to damage to a peripheral nerve __without autonomic change__ (Ex: postherpetic neuralgia, neuroma formation). 3) Central pain arises from abnormal central nervous system (CNS) activity (Ex: phantom limb pain, pain from spinal cord injuries, and post-stroke pain).
 * Chronic Pain ** : Pain of any etiology not directly related to neoplastic involvement, extending in duration beyond the expected temporal boundary of tissue injury and normal healing and adversely affecting the function or well-being of the individual.
 * Hyperalgesia - Increased response to a stimulus that normally is painful.
 * Hypoalgesia - Diminished response to a normally painful stimulus.
 * Analgesia - Absence of pain in response to stimulation that normally is painful.
 * Hyperesthesia - An abnormal or pathological increase in sensitivity to stimulation
 * Hypesthesia - Diminished sensitivity to stimulation
 * Dysesthesia - An unpleasant abnormal sensation, whether spontaneous or evoked.
 * Paresthesia - An abnormal sensation, whether spontaneous or evoked.
 * Allodynia — Pain resulting from a stimulus (such as light touch) that does not normally elicit pain.
 * Types of Neuropathic Pain: **


 * Mechanism of Persistent chronic Pain ** — Multiple mechanisms promote or facilitate persistent of chronic pain. These include peripheral sensitization, central sensitization, ectopic excitability, structural reorganization/phenotypic switch of neurons, primary sensory degeneration, Immune activation and disinhibition.

**Peripheral sensitization** — It refers to a reduction in the threshold and increase in the responsiveness of the peripheral terminals of nociceptors to nonnoxious stimuli.Tissue inflammation may release intracellular contents and synthesize substances including cytokines, chemokines, bradykinin, histamine, prostaglandins, and growth factors which result in changes in the chemical environment of the peripheral terminal of nociceptors. Proinflammatory mediators at the site of injury directly activate the nociceptor terminal and produce pain, others sensitize the terminal so that it becomes hypersensitive to subsequent stimuli.

Axonal injury would cause the release of soluble pain producing factors which increase nerve membrane excitability.

The glutamate-activated N-methyl-D-aspartic acid (NMDA) receptor is integral to this central sensitization processing.
 * Central sensitization ** — Central sensitization amplifies the synaptic transfer from the nociceptor terminal to dorsal horn neurons. Initial sensitization to synaptic transfer is activity-dependent, triggered by nociceptor input into the spinal cord. Later transcriptional changes in the molecular machinery of the dorsal cell sustain the sensitization beyond the initiating stimulus (ie, transcription-dependent). Thus, previously subthreshold synaptic inputs to nociceptive neurons now generate an augmented action potential output.

Sodium channel blockers play a role to reduce ectopic activity.
 * Ectopic Activity ** – Nerve injury would start activating sensory fibers to generate action potentials in the absence of any stimulation. Ectopic activity originates at multiple sites including neuroma and cell bodies of afferents in DRG and also in neighboring noninjured fibers. Na, K and Ca channels are upregulated after nerve injury. This leads to persistent burning, shooting pain, paresthesias.

After nerve injury physical rearrangement of this circuitry may occur. Additionally, after peripheral nerve injury, the neuromodulators brain-derived neurotrophic factor (BDNF) and substance P, normally expressed only in C-fibers, may begin to be expressed in large-diameter A fiber neurons.
 * Structural reorganization/phenotypic switch ** — Nerve injury may result in an altered profile of sensory neurons. The central terminals of nociceptor sensory neurons terminate in the most superficial laminae of the dorsal horn in the spinal cord. In contrast, low threshold sensory fibers activated by touch, pressure, vibration, and normal ranges of movement of joints terminate in the deep laminae of the dorsal horn.


 * Disinhibition ** — A reduction in inhibition can have an effect similar to increased excitability. GABA or glycine plays a role in inhibition.

**Glial Activation** – Nerve injury leads to activation of microglia in the dorsal horn. Microglia becomes highly mobile and begin secreting cytokines, chemokines and other neuromodulators which alters the function of neurons.