Substance P: Difference between revisions

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The most investigated role of SP has been in the perception of pain, although its effects seem to be more complex than simply "more means more pain." SP is abundant in the spinal cord, where it is synthesized in the spinal ganglia and transported centrally to the substantia gelatinosa and peripherally to nerve endings in many areas of the human body. Substance P elicits powerful currents from pain sensors to the spinal cord following noxious stimuli.<ref name="pain" /> Nociception is usually mediated by C and Aδ fibers which are activated by painful stimuli. SP performs a central role in this pathway. Aβ fibers normally send innocent tactile sensations from the periphery to the central nervous system, but inflammation can cause hypersensitivity to pain and it has been demonstrated that a subset of Aβ fibers will switch their phenotype to one that expresses SP, and thus become more pain-like, in the presence of inflammation.<ref>Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons | http://www.nature.com/nature/journal/v384/n6607/abs/384360a0.html</ref>

A number of NK1 receptor antagonists have been developed and tested for analgesic purposes with limited success.<ref name="analgesia">NK1 (substance P) receptor antagonists – why are they not analgesic in humans?| http://www.sciencedirect.com/science/article/pii/S0165614700015029</ref> Although preclinical data from animal experiments indicated that NK1 antagonists should produce pain relief in humans, NK1 antagonists proved to be for the most part completely ineffective as analgesics in humans. This is despite the fact that they showed a similar effect profile in animal tests to that of established analgesics like non-steroidal anti-inflammatory ~~substances~~ (NSAIDs). In addition, the same animal models translated successfully into clinically effective antiemetic drugs. There could be a number of explanations for this; the simplest one being that pain perception is a complex phenomenon in which no one receptor or neurotransmitter is solely responsible. Others include differences in the pharmacology of NKAs in animals and humans, the role of NK2 and NK3 receptors, and the blurring of the lines between stress and pain, as Substance P is also heightened in stressful situations.

A number of NK1 receptor antagonists have been developed and tested for analgesic purposes with limited success.<ref name="analgesia">NK1 (substance P) receptor antagonists – why are they not analgesic in humans?| http://www.sciencedirect.com/science/article/pii/S0165614700015029</ref> Although preclinical data from animal experiments indicated that NK1 antagonists should produce pain relief in humans, NK1 antagonists proved to be for the most part completely ineffective as analgesics in humans. This is despite the fact that they showed a similar effect profile in animal tests to that of established analgesics like non-steroidal anti-inflammatory drugs (NSAIDs). In addition, the same animal models translated successfully into clinically effective antiemetic drugs. There could be a number of explanations for this; the simplest one being that pain perception is a complex phenomenon in which no one receptor or neurotransmitter is solely responsible. Others include differences in the pharmacology of NKAs in animals and humans, the role of NK2 and NK3 receptors, and the blurring of the lines between stress and pain, as Substance P is also heightened in stressful situations.

A link between the chronic pain condition fibromyalgia and depression has been postulated.<ref>http://europepmc.org/abstract/med/1433012</ref><ref>http://europepmc.org/abstract/med/10648041</ref> This may or may not reflect a common biochemical link. In this context, the relevant point is that [[pregabalin]], which reduces the release of a number of neurotransmitters including Substance P, has been found to be effective in the treatment of fibromyalgia.<ref>http://onlinelibrary.wiley.com/doi/10.1002/art.20983/full</ref>

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There is ample circumstantial evidence that elevated SP is involved in reactions to stress and the regulation of mood.<ref name="mood" /> These include the presence of NK1 receptors in emotion centers like the amygdala and the association of SP-neurons with serotonergic or noradrenergic neurons; both serotonin and norepinephrine are heavily implicated in mood order and disorders like anxiety and depression. Elsewhere in the nervous system, SP associates with [[glutamate]], particularly the [[NMDA]] receptor. Disruptions of the glutamatergic system have recently been explored for their possible causal role in mood disorders.

Attempts have been made to create anxiolytic and antidepressant ~~substances~~ out of SP antagonists. Several phase I and II trials of NK1 antagonists, including aprepitant, showed significant antidepressant and anxiolytic activity in depressed patients. However, subsequent phase III trials failed to replicate the findings, and no antidepressant with a mechanism of action related to Substance P has been brought to market.<ref name="psychiatry">Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/15813642</ref>

Attempts have been made to create anxiolytic and antidepressant drugs out of SP antagonists. Several phase I and II trials of NK1 antagonists, including aprepitant, showed significant antidepressant and anxiolytic activity in depressed patients. However, subsequent phase III trials failed to replicate the findings, and no antidepressant with a mechanism of action related to Substance P has been brought to market.<ref name="psychiatry">Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/15813642</ref>

Male knockout mice were significantly less aggressive when faced with an invasion of their territory compared to wild-type mice, indicating a role in modulating social function.<ref name="stress" />

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==Drugs that target Substance P==

Due to its association with largely negative phenomena (pain, stress responses, affective disorders, and vomiting), ~~substance~~ development has been focused on Substance P antagonists. Since SP is a high-affinity ligand for the NK1 receptor, NK1 receptor antagonists were the first to be developed. However, SP also binds to NK2 and NK3 receptors and related neuropeptides have higher affinity for these receptors, so development of antagonists for these receptors has also been pursued. There are a number of NK1 antagonists attested in the medical literature, but few of them are in use. They include:

Due to its association with largely negative phenomena (pain, stress responses, affective disorders, and vomiting), drug development has been focused on Substance P antagonists. Since SP is a high-affinity ligand for the NK1 receptor, NK1 receptor antagonists were the first to be developed. However, SP also binds to NK2 and NK3 receptors and related neuropeptides have higher affinity for these receptors, so development of antagonists for these receptors has also been pursued. There are a number of NK1 antagonists attested in the medical literature, but few of them are in use. They include:

* Aprepitant is a failed antidepressant that succeeded in clinical trials for chemotherapy-induced vomiting and nausea (CIVN) and was FDA approved for treating CIVN in 2004.

@@ Line 19: / Line 19: @@
 The most investigated role of SP has been in the perception of pain, although its effects seem to be more complex than simply "more means more pain." SP is abundant in the spinal cord, where it is synthesized in the spinal ganglia and transported centrally to the substantia gelatinosa and peripherally to nerve endings in many areas of the human body. Substance P elicits powerful currents from pain sensors to the spinal cord following noxious stimuli.<ref name="pain" /> Nociception is usually mediated by C and Aδ fibers which are activated by painful stimuli. SP performs a central role in this pathway. Aβ fibers normally send innocent tactile sensations from the periphery to the central nervous system, but inflammation can cause hypersensitivity to pain and it has been demonstrated that a subset of Aβ fibers will switch their phenotype to one that expresses SP, and thus become more pain-like, in the presence of inflammation.<ref>Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons | http://www.nature.com/nature/journal/v384/n6607/abs/384360a0.html</ref>
-A number of NK1 receptor antagonists have been developed and tested for analgesic purposes with limited success.<ref name="analgesia">NK1 (substance P) receptor antagonists – why are they not analgesic in humans?| http://www.sciencedirect.com/science/article/pii/S0165614700015029</ref> Although preclinical data from animal experiments indicated that NK1 antagonists should produce pain relief in humans, NK1 antagonists proved to be for the most part completely ineffective as analgesics in humans. This is despite the fact that they showed a similar effect profile in animal tests to that of established analgesics like non-steroidal anti-inflammatory substances (NSAIDs). In addition, the same animal models translated successfully into clinically effective antiemetic drugs. There could be a number of explanations for this; the simplest one being that pain perception is a complex phenomenon in which no one receptor or neurotransmitter is solely responsible. Others include differences in the pharmacology of NKAs in animals and humans, the role of NK2 and NK3 receptors, and the blurring of the lines between stress and pain, as Substance P is also heightened in stressful situations.
+A number of NK1 receptor antagonists have been developed and tested for analgesic purposes with limited success.<ref name="analgesia">NK1 (substance P) receptor antagonists – why are they not analgesic in humans?| http://www.sciencedirect.com/science/article/pii/S0165614700015029</ref> Although preclinical data from animal experiments indicated that NK1 antagonists should produce pain relief in humans, NK1 antagonists proved to be for the most part completely ineffective as analgesics in humans. This is despite the fact that they showed a similar effect profile in animal tests to that of established analgesics like non-steroidal anti-inflammatory drugs (NSAIDs). In addition, the same animal models translated successfully into clinically effective antiemetic drugs. There could be a number of explanations for this; the simplest one being that pain perception is a complex phenomenon in which no one receptor or neurotransmitter is solely responsible. Others include differences in the pharmacology of NKAs in animals and humans, the role of NK2 and NK3 receptors, and the blurring of the lines between stress and pain, as Substance P is also heightened in stressful situations.
 A link between the chronic pain condition fibromyalgia and depression has been postulated.<ref>http://europepmc.org/abstract/med/1433012</ref><ref>http://europepmc.org/abstract/med/10648041</ref> This may or may not reflect a common biochemical link. In this context, the relevant point is that [[pregabalin]], which reduces the release of a number of neurotransmitters including Substance P, has been found to be effective in the treatment of fibromyalgia.<ref>http://onlinelibrary.wiley.com/doi/10.1002/art.20983/full</ref>
@@ Line 43: / Line 43: @@
 There is ample circumstantial evidence that elevated SP is involved in reactions to stress and the regulation of mood.<ref name="mood" /> These include the presence of NK1 receptors in emotion centers like the amygdala and the association of SP-neurons with serotonergic or noradrenergic neurons; both serotonin and norepinephrine are heavily implicated in mood order and disorders like anxiety and depression. Elsewhere in the nervous system, SP associates with [[glutamate]], particularly the [[NMDA]] receptor. Disruptions of the glutamatergic system have recently been explored for their possible causal role in mood disorders.
-Attempts have been made to create anxiolytic and antidepressant substances out of SP antagonists. Several phase I and II trials of NK1 antagonists, including aprepitant, showed significant antidepressant and anxiolytic activity in depressed patients. However, subsequent phase III trials failed to replicate the findings, and no antidepressant with a mechanism of action related to Substance P has been brought to market.<ref name="psychiatry">Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/15813642</ref>
+Attempts have been made to create anxiolytic and antidepressant drugs out of SP antagonists. Several phase I and II trials of NK1 antagonists, including aprepitant, showed significant antidepressant and anxiolytic activity in depressed patients. However, subsequent phase III trials failed to replicate the findings, and no antidepressant with a mechanism of action related to Substance P has been brought to market.<ref name="psychiatry">Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/15813642</ref>
 Male knockout mice were significantly less aggressive when faced with an invasion of their territory compared to wild-type mice, indicating a role in modulating social function.<ref name="stress" />
@@ Line 57: / Line 57: @@
 ==Drugs that target Substance P==
-Due to its association with largely negative phenomena (pain, stress responses, affective disorders, and vomiting), substance development has been focused on Substance P antagonists. Since SP is a high-affinity ligand for the NK1 receptor, NK1 receptor antagonists were the first to be developed. However, SP also binds to NK2 and NK3 receptors and related neuropeptides have higher affinity for these receptors, so development of antagonists for these receptors has also been pursued. There are a number of NK1 antagonists attested in the medical literature, but few of them are in use. They include:
+Due to its association with largely negative phenomena (pain, stress responses, affective disorders, and vomiting), drug development has been focused on Substance P antagonists. Since SP is a high-affinity ligand for the NK1 receptor, NK1 receptor antagonists were the first to be developed. However, SP also binds to NK2 and NK3 receptors and related neuropeptides have higher affinity for these receptors, so development of antagonists for these receptors has also been pursued. There are a number of NK1 antagonists attested in the medical literature, but few of them are in use. They include:
 * Aprepitant is a failed antidepressant that succeeded in clinical trials for chemotherapy-induced vomiting and nausea (CIVN) and was FDA approved for treating CIVN in 2004.