When diagnosing pain it can be categorized into the following qualities:
1. Physiological pain
2. Acute or chronic pain
3. Inflammatory pain, and
4. Neuropathic pain.
On the other hand pain can be divided into different categories depending on its origin:
1. Transient-stimulus induced pain
2. Pain from tissue damage
3. Pain from injury of afferent neurons
4. Pain from injury of central neurons.
Everything should be done in order to identify the mechanisms of chronification, which may be due to:
1. Nociceptor activation
2. Nociceptor sensitization
3. Central sensitization
5. Ectopic activity
6. Structural reorganization, and/or
Acute pain sensations are transmitted from the periphery to the brain. At the level of the spinal cord, ascending pain signals are modulated by afferent signals from touch receptors. Nociceptors release glutamate and substance P in layers I, II (substantia gelatinosa) and III that stimulate both NMDA- and AMPA-(glutamate) receptors and NK1-(neurokinin) receptors on spinal output neurons. As a consequence of NMDA receptor activation, two potent mediators of pain, nitric oxide and adenosine, are produced. The glutaminergic neurons (AB-fibers) carrying somatosensory information from touch receptors synapse in laminae III and IV onto dendrites of spinal output neurons that become the contralateral spinothalamic tract carrying the pain, temperature, and touch signals to the higher levels of the CNS (Figure I-3).
The mechanisms underlying chronic pain (i.e. neuropathic pain) may be either peripheral (e.g. reflex sympathetic dystrophy) or central (e.g. postherpetic neuralgia). For instance, following peripheral injury and inflammation, repetitive firing of C-fibers lead to activation of NMDA glutaminergic receptors, and C-fiber-evoked "wind-up" in which the C-fiber response is highly augmented to subsequent input. NMDA receptor antagonists can block this phenomenon. The C-fiber-evoked "wind-up" results in hypersensitization with expansion of receptive fields of nociceptive input and hence the induction of spontaneous pain and hyper-algesia (excessive sensitivity to noxious stimuli). In addition, allodynia, a condition under which an ordinarily non-painful stimulus evokes pain, results from the activation of AB-fibers by innocuous tactile stimuli. Peripheral mechanisms also include collateral sprouting from primary nociceptive afferents.
All these mechanisms add up to "wind up", including:
1. Excitotoxicity in layers l and II of dorsal horn neurons;
2. reorganization of dorsal horn synaptic connectivity, characterized by sprouting of large myelinated AB-afferents into lamina II of the dorsal horn;
3. spontaneous discharge in spinal cord neurons, and
4. a lowered threshold in the spinothalamic tract neurons and the next relay station, the thalamus.
Aside from commonly known transmitters in mediation of afferent pain sensation, such as substance P, recent discoveries have identified a number of additional mediators and target sites, all of which presently are under scrutinization for possible therapy:
1. Neurotropins, with its typical ligand, the nerve growth factor and the respectable receptor site.
2. Interleukin 6, interferon-^ receptors, PGI2 and its receptors, B2 bradykinin receptors, tachykinin receptors, A2A adenosine receptors as peripheral mediators of nociception and hyperalgesia.
3. Opioids and their receptors: e.g. B-endorphin, enkephalins, orphanin FQ/nociceptin, dynorphin, k- and 8-opioid receptors.
4. Non-opioid neurotransmitter receptors like adrenergic and serotonin receptor ligands.
5. Intracellular molecules participating in signal transduction such as protein kinase A and protein kinase Cg, nitric oxide synthetase (NOS), heterotrimeric Go proteins.
6. Selective ligands for the CB1 cannabinoid receptor.
7. Selective ligands for the VRj vanilloid receptor.
9. Calcium ion channels of the N- and R-type, as well as voltage-gated (or inward rectifying) sodium and potassium channels, all of which play an important part in the mediation of nociceptive afferents. In addition,
10. ligands for the Hj-histamine receptor, a
11. specific galanin-like mediators, and
12. ligands that bind to the P2X3 (nucleotide-gated, inotropic) receptors.
All such ligands presently are under investigation as new targets in pain therapy.
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