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[[File:Substance P.svg| | [[File:Substance P.svg|thumb|right|400px||The molecular structure of Substance P.]] | ||
'''Substance P''' (SP) is a neuropeptide that functions as a neurotransmitter and neuromodulator affecting the neurokinin receptors. It has most closely been associated with nociception (pain perception),<ref name="pain">Substance P: | '''Substance P''' (SP) is a neuropeptide that functions as a neurotransmitter and neuromodulator affecting the neurokinin receptors. It has most closely been associated with nociception (pain perception),<ref name="pain">{{cite journal | vauthors=((Zubrzycka, M.)), ((Janecka, A.)) | journal=Endocrine Regulations | title=Substance P: transmitter of nociception (Minireview) | volume=34 | issue=4 | pages=195–201 | date= December 2000 | issn=1210-0668}}</ref> but seems to have a wide range of effects including an important role in nausea, emesis (vomiting), the rewarding effects of opiates, and likely in regulating stress responses and anxiety/depression-related behavior.<ref name="mood">{{cite journal | vauthors=((Ebner, K.)), ((Singewald, N.)) | journal=Amino Acids | title=The role of substance P in stress and anxiety responses | volume=31 | issue=3 | pages=251–272 | date= October 2006 | url=http://link.springer.com/10.1007/s00726-006-0335-9 | issn=0939-4451 | doi=10.1007/s00726-006-0335-9}}</ref> SP is found throughout the body, in the brain, peripheral nerve endings and the spine. The full extent of its involvement in neurotransmission and its possible therapeutic or recreational implications is unclear. | ||
==Chemical composition== | ==Chemical composition== | ||
| Line 9: | Line 9: | ||
==Receptor== | ==Receptor== | ||
SP has high affinity for the Neurokinin 1 receptor (NK1), although it also activates NK2 and NK3. NK1 receptors are often located on neurons that also express [[norepinephrine]] or [[serotonin]] receptors | SP has high affinity for the Neurokinin 1 receptor (NK1), although it also activates NK2 and NK3. NK1 receptors are often located on neurons that also express [[norepinephrine]] or [[serotonin]] receptors and is found in brain regions known to be involved in emotional responses, such as the hippocampus and amygdala.<ref name="mood" /> | ||
===Function as a neurotransmitter or neuromodulator=== | ===Function as a neurotransmitter or neuromodulator=== | ||
Substance P does not function like a typical neurotransmitter. There exists no SP transporter to pump the peptide back into the axon terminal, unlike neurotransmitters like dopamine or serotonin which have protein pumps that function to recycle the neurotransmitter once it has left the receptor. Instead, SP must be | Substance P does not function like a typical neurotransmitter. There exists no SP transporter to pump the peptide back into the axon terminal, unlike neurotransmitters like [[dopamine]] or [[serotonin]] which have protein pumps that function to recycle the neurotransmitter once it has left the receptor. Instead, SP must be synthesised from scratch again. However, SP is believed to be released beyond the synapse and may diffuse over larger distances than traditional neurotransmitters, which are limited to the [[synapse]], the tiny gap between one neuron on the sending end and one on the receiving one. Certain regions of the brain have many NK1 receptors but little Substance P or vice versa, which may have different explanations. One possible explanation is that SP may float over larger distances and subsist in the plasma surrounding cells for longer periods of time. | ||
==Role in pain perception and interaction with opioids== | ==Role in pain perception and interaction with opioids== | ||
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 | 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>{{cite journal | vauthors=((Neumann, S.)), ((Doubell, T. P.)), ((Leslie, T.)), ((Woolf, C. J.)) | journal=Nature | title=Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons | volume=384 | issue=6607 | pages=360–364 | date= November 1996 | url=https://www.nature.com/articles/384360a0 | issn=1476-4687 | doi=10.1038/384360a0}}</ref> | ||
A number of NK1 receptor antagonists have been developed and tested for analgesic purposes | A number of NK1 receptor antagonists have been developed and tested for analgesic purposes with limited success.<ref name="analgesia">{{cite journal | vauthors=((Hill, R.)) | journal=Trends in Pharmacological Sciences | title=NK1 (substance P) receptor antagonists – why are they not analgesic in humans? | volume=21 | issue=7 | pages=244–246 | date=1 July 2000 | url=https://www.sciencedirect.com/science/article/pii/S0165614700015029 | issn=0165-6147 | doi=10.1016/S0165-6147(00)01502-9}}</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> | A link between the chronic pain condition fibromyalgia and depression has been postulated.<ref>{{cite journal | vauthors=((Kravitz, H. M.)), ((Katz, R.)), ((Kot, E.)), ((Helmke, N.)), ((Fawcett, J.)) | journal=The Journal of rheumatology | title=Biochemical clues to a fibromyalgia-depression link: imipramine binding in patients with fibromyalgia or depression and in healthy controls | volume=19 | issue=9 | pages=1428–1432 | date=1 September 1992 | issn=0315-162X}}</ref><ref>{{cite journal | vauthors=((Okifuji, A.)), ((Turk, D. C.)), ((Sherman, J. J.)) | journal=The Journal of rheumatology | title=Evaluation of the relationship between depression and fibromyalgia syndrome: why aren’t all patients depressed | volume=27 | issue=1 | pages=212–219 | date=1 January 2000 | issn=0315-162X}} | ||
</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>{{cite journal | vauthors=((Crofford, L. J.)), ((Rowbotham, M. C.)), ((Mease, P. J.)), ((Russell, I. J.)), ((Dworkin, R. H.)), ((Corbin, A. E.)), ((Young, J. P.)), ((LaMoreaux, L. K.)), ((Martin, S. A.)), ((Sharma, U.)) | journal=Arthritis & Rheumatism | title=Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial | volume=52 | issue=4 | pages=1264–1273 | date= April 2005 | url=https://onlinelibrary.wiley.com/doi/10.1002/art.20983 | issn=0004-3591 | doi=10.1002/art.20983}}</ref> | |||
But Substance P can also modulate pain relief positively. Various stressors can induce analgesia. Short-term pain relief can facilitate the execution of the fight of flight response. Mice forced to swim in cold water develop short-term analgesia, but this response was significantly reduced in knockout mice. <ref name="stress"> | But Substance P can also modulate pain relief positively. Various stressors can induce analgesia. Short-term pain relief can facilitate the execution of the fight of flight response. Mice forced to swim in cold water develop short-term analgesia, but this response was significantly reduced in knockout mice.<ref name="stress">{{cite journal | vauthors=((Felipe, C. D.)), ((Herrero, J. F.)), ((O’Brien, J. A.)), ((Palmer, J. A.)), ((Doyle, C. A.)), ((Smith, A. J. H.)), ((Laird, J. M. A.)), ((Belmonte, C.)), ((Cervero, F.)), ((Hunt, S. P.)) | journal=Nature | title=Altered nociception, analgesia and aggression in mice lacking the receptor for substance P | volume=392 | issue=6674 | pages=394–397 | date= March 1998 | url=https://www.nature.com/articles/32904 | issn=1476-4687 | doi=10.1038/32904}}</ref> Thus, in this instance, the presence of SP enhanced the pain relief induced by the stressor. | ||
In acid-induced chronic muscle pain, SP has a surprising analgesic effect.<ref> | In acid-induced chronic muscle pain, SP has a surprising analgesic effect.<ref>{{cite journal | vauthors=((Lin, C.-C. J.)), ((Chen, W.-N.)), ((Chen, C.-J.)), ((Lin, Y.-W.)), ((Zimmer, A.)), ((Chen, C.-C.)) | journal=Proceedings of the National Academy of Sciences | title=An antinociceptive role for substance P in acid-induced chronic muscle pain | volume=109 | issue=2 | date=10 January 2012 | url=https://pnas.org/doi/full/10.1073/pnas.1108903108 | issn=0027-8424 | doi=10.1073/pnas.1108903108}}</ref> | ||
===Interaction with opioids=== | ===Interaction with opioids=== | ||
In NK1 knockout mice, i.e., mice that had been genetically altered not to express Substance P's preferred receptor, the rewarding effects of morphine were absent.<ref name="absent">Rewarding effects of opiates are absent in mice lacking the receptor for substance P | | In NK1 knockout mice, i.e., mice that had been genetically altered not to express Substance P's preferred receptor, the rewarding effects of morphine were absent.<ref name="absent">{{cite journal | vauthors=((Murtra, P.)), ((Sheasby, A. M.)), ((Hunt, S. P.)), ((De Felipe, C.)) | journal=Nature | title=Rewarding effects of opiates are absent in mice lacking the receptor for substance P | volume=405 | issue=6783 | pages=180–183 | date= May 2000 | url=https://www.nature.com/articles/35012069 | issn=1476-4687 | doi=10.1038/35012069}}</ref> Mice learned to associate one of two compartments with the drug. Wild-type mice developed a strong place preference for the morphine compartment, whereas NK1 knockout mice did not. Opioid-dependent mice were also conditioned to associate one compartment with withdrawal induced by the injection of [[naloxone]]. Wild-type mice developed a strong aversion for the withdrawal compartment, whereas NK1 knockout mice showed significantly less avoidance of that compartment. Thus, at least in preclinical animal trials, SP appears to be important both in the positive reinforcement effects of opiates and the negative effects of withdrawal. The physical signs of withdrawal were still present in both wild-type and knockout mice, except for jumping behavior (considered a dominant motor sign of opiate withdrawal in mice) which was not present in knockout mice. | ||
Morphine inhibits the release of SP in the spinal cord.<ref>Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo | | Morphine inhibits the release of SP in the spinal cord.<ref>{{cite journal | vauthors=((Yaksh, T. L.)), ((Jessell, T. M.)), ((Gamse, R.)), ((Mudge, A. W.)), ((Leeman, S. E.)) | journal=Nature | title=Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo | volume=286 | issue=5769 | pages=155–157 | date= July 1980 | url=https://www.nature.com/articles/286155a0 | issn=1476-4687 | doi=10.1038/286155a0}}</ref> | ||
==Role in emesis== | ==Role in emesis== | ||
Substance P appears to have an important role in nausea and vomiting. In 2004, the NK1 antagonist '''aprepitant''' (brand name '''Emend''') was approved by the | Substance P appears to have an important role in nausea and vomiting. In 2004, the NK1 antagonist '''aprepitant''' (brand name '''Emend''') was approved by the U.S. FDA for the treatment of chemotherapy-induced nausea and vomiting.<ref>{{Citation | title=Drug Approval Package: EMEND (Aprepitant) NDA #21-549 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-549_Emend.cfm}}</ref> In 2014, a novel NK1 antagonist, netupitant, was FDA approved in a preparation with another antiemetic agent, palonosetron (a 5-HT3 antagonist), for the same purpose.<ref>http://www.drugs.com/newdrugs/fda-approves-akynzeo-netupitant-palonosetron-chemotherapy-induced-nausea-vomiting-4096.html</ref> | ||
The motor nucleus of the vagal nerve in the medulla controls functions in the gastrointestinal tract and abdomen | The motor nucleus of the [[vagal nerve]] in the medulla controls functions in the gastrointestinal tract and abdomen and NK1 activation in this area potently invokes relaxation of the fundus, the upper part of the stomach. This relaxation is essential to vomiting, and it has been speculated that the efficacy of SP antagonists in inhibiting vomiting is due to inhibiting this relaxation via the medulla.<ref>{{cite journal | vauthors=((Hornby, P. J.)) | journal=The American Journal of Medicine | title=Central neurocircuitry associated with emesis | volume=111 | issue=8, Supplement 1 | pages=106–112 | date=3 December 2001 | url=https://www.sciencedirect.com/science/article/pii/S000293430100849X | issn=0002-9343 | doi=10.1016/S0002-9343(01)00849-X}}</ref> | ||
==Role in the regulation of emotions and stress== | ==Role in the regulation of emotions and stress== | ||
| Line 43: | Line 44: | ||
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. | 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 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 | | 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">{{cite journal | vauthors=((Herpfer, I.)), ((Lieb, K.)) | journal=CNS drugs | title=Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential | volume=19 | issue=4 | pages=275–293 | date= 2005 | issn=1172-7047 | doi=10.2165/00023210-200519040-00001}}</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" /> | 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 49: | Line 50: | ||
==Other roles== | ==Other roles== | ||
In vitro, Substance P increased the proliferation of rat neural progenitor cells.<ref> | In vitro, Substance P increased the proliferation of rat neural progenitor cells.<ref>{{cite journal | vauthors=((Park, S.-W.)), ((Yan, Y.-P.)), ((Satriotomo, I.)), ((Vemuganti, R.)), ((Dempsey, R. J.)) | journal=Journal of Neurosurgery | title=Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions | volume=107 | issue=3 | pages=593–599 | date=1 September 2007 | url=https://thejns.org/view/journals/j-neurosurg/107/3/article-p593.xml | doi=10.3171/JNS-07/09/0593}}</ref> In other words, SP increases neuroplasticity. | ||
SP also encourages the growth of epithelial cells in vitro.<ref> | SP also encourages the growth of epithelial cells in vitro.<ref>{{cite journal | vauthors=((Reid, T. W.)), ((Murphy, C. J.)), ((Iwahashi, C. K.)), ((Foster, B. A.)), ((Mannis, M. J.)) | journal=Journal of Cellular Biochemistry | title=Stimulation of epithelial cell growth by the neuropeptide substance P | volume=52 | issue=4 | pages=476–485 | date= August 1993 | issn=0730-2312 | doi=10.1002/jcb.240520411}}</ref> | ||
SP is a vasodilator.<ref> | SP is a vasodilator.<ref>{{cite journal | vauthors=((Tagawa, T.)), ((Mohri, M.)), ((Tagawa, H.)), ((Egashira, K.)), ((Shimokawa, H.)), ((Kuga, T.)), ((Hirooka, Y.)), ((Takeshita, A.)) | journal=Journal of Cardiovascular Pharmacology | title=Role of nitric oxide in substance P-induced vasodilation differs between the coronary and forearm circulation in humans | volume=29 | issue=4 | pages=546–553 | date= April 1997 | issn=0160-2446 | doi=10.1097/00005344-199704000-00017}}</ref> | ||
==Drugs that target Substance P== | ==Drugs that target Substance P== | ||
Due to its association with largely negative phenomena (pain, stress responses | 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 | * 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. | ||
* Netupitant | * Netupitant is FDA approved for CIVN in a combination product with another antiemetic, palonosetron, in 2014. | ||
* CP-99,994 | * CP-99,994 which reached phase II clinical trials for dental pain. It was able to replicate the effect of ibuprofen on postoperative dental pain,<ref>{{cite journal | vauthors=((Dionne, R. A.)), ((Max, M. B.)), ((Gordon, S. M.)), ((Parada, S.)), ((Sang, C.)), ((Gracely, R. H.)), ((Sethna, N. F.)), ((MacLean, D. B.)) | journal=Clinical Pharmacology & Therapeutics | title=The substance P receptor antagonist CP-99,994 reduces acute postoperative pain* | volume=64 | issue=5 | pages=562–568 | date= November 1998 | url=http://doi.wiley.com/10.1016/S0009-9236(98)90140-0 | issn=0009-9236 | doi=10.1016/S0009-9236(98)90140-0}}</ref> but trials were discontinued due to poor oral bioavailability. | ||
* Maropitant (brand name '''Cerenia''') | * Maropitant (brand name '''Cerenia''') is FDA approved for treatment and prevention of vomiting in cats and dogs.<ref>{{Citation | title=Cerenia - Zoetis Inc.: Veterinary Package Insert | url=https://vetlabel.com/lib/vet/meds/cerenia/}}</ref> | ||
* Vestipitant | * Vestipitant is currently under development for use against, among other things, insomnia.<ref>{{cite journal | vauthors=((Ratti, E.)), ((Carpenter, D. J.)), ((Zamuner, S.)), ((Fernandes, S.)), ((Squassante, L.)), ((Danker-Hopfe, H.)), ((Archer, G.)), ((Robertson, J.)), ((Alexander, R.)), ((Trist, D. G.)), ((Merlo-Pich, E.)) | journal=Sleep | title=Efficacy of Vestipitant, A Neurokinin-1 Receptor Antagonist, in Primary Insomnia | volume=36 | issue=12 | pages=1823–1830 | date=1 December 2013 | url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825431/ | issn=0161-8105 | doi=10.5665/sleep.3208}}</ref> | ||
* Fosaprepitant | * Fosaprepitant is a [[prodrug]] for aprepitant. | ||
==See also== | ==See also== | ||
* [[Responsible use]] | |||
* [[Neurotransmitter]] | * [[Neurotransmitter]] | ||
* [[Receptor]] | * [[Receptor]] | ||
==External links== | |||
*[https://en.wikipedia.org/wiki/Substance_P Substance P (Wikipedia)] | |||
==References== | ==References== | ||
| Line 75: | Line 79: | ||
<references/> | <references/> | ||
[[Category: | [[Category:Neurotransmitter]] | ||
{{#set:Featured=true}} | |||
Latest revision as of 23:13, 21 April 2024
Substance P (SP) is a neuropeptide that functions as a neurotransmitter and neuromodulator affecting the neurokinin receptors. It has most closely been associated with nociception (pain perception),[1] but seems to have a wide range of effects including an important role in nausea, emesis (vomiting), the rewarding effects of opiates, and likely in regulating stress responses and anxiety/depression-related behavior.[2] SP is found throughout the body, in the brain, peripheral nerve endings and the spine. The full extent of its involvement in neurotransmission and its possible therapeutic or recreational implications is unclear.
Chemical composition
SP is an undecapeptide (a peptide consisting of eleven amino acid residues) composed of the amino acid chain Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met, with an amidation at the C-terminus. It is closely related to Neurokinin A (NKA), another neurologically active peptide. Both NKA and SP are encoded by the same mRNA, which when spliced together in different ways can produce either peptide.
Receptor
SP has high affinity for the Neurokinin 1 receptor (NK1), although it also activates NK2 and NK3. NK1 receptors are often located on neurons that also express norepinephrine or serotonin receptors and is found in brain regions known to be involved in emotional responses, such as the hippocampus and amygdala.[2]
Function as a neurotransmitter or neuromodulator
Substance P does not function like a typical neurotransmitter. There exists no SP transporter to pump the peptide back into the axon terminal, unlike neurotransmitters like dopamine or serotonin which have protein pumps that function to recycle the neurotransmitter once it has left the receptor. Instead, SP must be synthesised from scratch again. However, SP is believed to be released beyond the synapse and may diffuse over larger distances than traditional neurotransmitters, which are limited to the synapse, the tiny gap between one neuron on the sending end and one on the receiving one. Certain regions of the brain have many NK1 receptors but little Substance P or vice versa, which may have different explanations. One possible explanation is that SP may float over larger distances and subsist in the plasma surrounding cells for longer periods of time.
Role in pain perception and interaction with opioids
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.[1] 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.[3]
A number of NK1 receptor antagonists have been developed and tested for analgesic purposes with limited success.[4] 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.[5][6] 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.[7]
But Substance P can also modulate pain relief positively. Various stressors can induce analgesia. Short-term pain relief can facilitate the execution of the fight of flight response. Mice forced to swim in cold water develop short-term analgesia, but this response was significantly reduced in knockout mice.[8] Thus, in this instance, the presence of SP enhanced the pain relief induced by the stressor.
In acid-induced chronic muscle pain, SP has a surprising analgesic effect.[9]
Interaction with opioids
In NK1 knockout mice, i.e., mice that had been genetically altered not to express Substance P's preferred receptor, the rewarding effects of morphine were absent.[10] Mice learned to associate one of two compartments with the drug. Wild-type mice developed a strong place preference for the morphine compartment, whereas NK1 knockout mice did not. Opioid-dependent mice were also conditioned to associate one compartment with withdrawal induced by the injection of naloxone. Wild-type mice developed a strong aversion for the withdrawal compartment, whereas NK1 knockout mice showed significantly less avoidance of that compartment. Thus, at least in preclinical animal trials, SP appears to be important both in the positive reinforcement effects of opiates and the negative effects of withdrawal. The physical signs of withdrawal were still present in both wild-type and knockout mice, except for jumping behavior (considered a dominant motor sign of opiate withdrawal in mice) which was not present in knockout mice.
Morphine inhibits the release of SP in the spinal cord.[11]
Role in emesis
Substance P appears to have an important role in nausea and vomiting. In 2004, the NK1 antagonist aprepitant (brand name Emend) was approved by the U.S. FDA for the treatment of chemotherapy-induced nausea and vomiting.[12] In 2014, a novel NK1 antagonist, netupitant, was FDA approved in a preparation with another antiemetic agent, palonosetron (a 5-HT3 antagonist), for the same purpose.[13]
The motor nucleus of the vagal nerve in the medulla controls functions in the gastrointestinal tract and abdomen and NK1 activation in this area potently invokes relaxation of the fundus, the upper part of the stomach. This relaxation is essential to vomiting, and it has been speculated that the efficacy of SP antagonists in inhibiting vomiting is due to inhibiting this relaxation via the medulla.[14]
Role in the regulation of emotions and stress
There is ample circumstantial evidence that elevated SP is involved in reactions to stress and the regulation of mood.[2] 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 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.[15]
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.[8]
Other roles
In vitro, Substance P increased the proliferation of rat neural progenitor cells.[16] In other words, SP increases neuroplasticity.
SP also encourages the growth of epithelial cells in vitro.[17]
SP is a vasodilator.[18]
Drugs that target Substance P
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.
- Netupitant is FDA approved for CIVN in a combination product with another antiemetic, palonosetron, in 2014.
- CP-99,994 which reached phase II clinical trials for dental pain. It was able to replicate the effect of ibuprofen on postoperative dental pain,[19] but trials were discontinued due to poor oral bioavailability.
- Maropitant (brand name Cerenia) is FDA approved for treatment and prevention of vomiting in cats and dogs.[20]
- Vestipitant is currently under development for use against, among other things, insomnia.[21]
- Fosaprepitant is a prodrug for aprepitant.
See also
External links
References
- ↑ 1.0 1.1 Zubrzycka, M., Janecka, A. (December 2000). "Substance P: transmitter of nociception (Minireview)". Endocrine Regulations. 34 (4): 195–201. ISSN 1210-0668.
- ↑ 2.0 2.1 2.2 Ebner, K., Singewald, N. (October 2006). "The role of substance P in stress and anxiety responses". Amino Acids. 31 (3): 251–272. doi:10.1007/s00726-006-0335-9. ISSN 0939-4451.
- ↑ Neumann, S., Doubell, T. P., Leslie, T., Woolf, C. J. (November 1996). "Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons". Nature. 384 (6607): 360–364. doi:10.1038/384360a0. ISSN 1476-4687.
- ↑ Hill, R. (1 July 2000). "NK1 (substance P) receptor antagonists – why are they not analgesic in humans?". Trends in Pharmacological Sciences. 21 (7): 244–246. doi:10.1016/S0165-6147(00)01502-9. ISSN 0165-6147.
- ↑ Kravitz, H. M., Katz, R., Kot, E., Helmke, N., Fawcett, J. (1 September 1992). "Biochemical clues to a fibromyalgia-depression link: imipramine binding in patients with fibromyalgia or depression and in healthy controls". The Journal of rheumatology. 19 (9): 1428–1432. ISSN 0315-162X.
- ↑ Okifuji, A., Turk, D. C., Sherman, J. J. (1 January 2000). "Evaluation of the relationship between depression and fibromyalgia syndrome: why aren't all patients depressed". The Journal of rheumatology. 27 (1): 212–219. ISSN 0315-162X.
- ↑ Crofford, L. J., Rowbotham, M. C., Mease, P. J., Russell, I. J., Dworkin, R. H., Corbin, A. E., Young, J. P., LaMoreaux, L. K., Martin, S. A., Sharma, U. (April 2005). "Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial". Arthritis & Rheumatism. 52 (4): 1264–1273. doi:10.1002/art.20983. ISSN 0004-3591.
- ↑ 8.0 8.1 Felipe, C. D., Herrero, J. F., O’Brien, J. A., Palmer, J. A., Doyle, C. A., Smith, A. J. H., Laird, J. M. A., Belmonte, C., Cervero, F., Hunt, S. P. (March 1998). "Altered nociception, analgesia and aggression in mice lacking the receptor for substance P". Nature. 392 (6674): 394–397. doi:10.1038/32904. ISSN 1476-4687.
- ↑ Lin, C.-C. J., Chen, W.-N., Chen, C.-J., Lin, Y.-W., Zimmer, A., Chen, C.-C. (10 January 2012). "An antinociceptive role for substance P in acid-induced chronic muscle pain". Proceedings of the National Academy of Sciences. 109 (2). doi:10.1073/pnas.1108903108. ISSN 0027-8424.
- ↑ Murtra, P., Sheasby, A. M., Hunt, S. P., De Felipe, C. (May 2000). "Rewarding effects of opiates are absent in mice lacking the receptor for substance P". Nature. 405 (6783): 180–183. doi:10.1038/35012069. ISSN 1476-4687.
- ↑ Yaksh, T. L., Jessell, T. M., Gamse, R., Mudge, A. W., Leeman, S. E. (July 1980). "Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo". Nature. 286 (5769): 155–157. doi:10.1038/286155a0. ISSN 1476-4687.
- ↑ Drug Approval Package: EMEND (Aprepitant) NDA #21-549
- ↑ http://www.drugs.com/newdrugs/fda-approves-akynzeo-netupitant-palonosetron-chemotherapy-induced-nausea-vomiting-4096.html
- ↑ Hornby, P. J. (3 December 2001). "Central neurocircuitry associated with emesis". The American Journal of Medicine. 111 (8, Supplement 1): 106–112. doi:10.1016/S0002-9343(01)00849-X. ISSN 0002-9343.
- ↑ Herpfer, I., Lieb, K. (2005). "Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential". CNS drugs. 19 (4): 275–293. doi:10.2165/00023210-200519040-00001. ISSN 1172-7047.
- ↑ Park, S.-W., Yan, Y.-P., Satriotomo, I., Vemuganti, R., Dempsey, R. J. (1 September 2007). "Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions". Journal of Neurosurgery. 107 (3): 593–599. doi:10.3171/JNS-07/09/0593.
- ↑ Reid, T. W., Murphy, C. J., Iwahashi, C. K., Foster, B. A., Mannis, M. J. (August 1993). "Stimulation of epithelial cell growth by the neuropeptide substance P". Journal of Cellular Biochemistry. 52 (4): 476–485. doi:10.1002/jcb.240520411. ISSN 0730-2312.
- ↑ Tagawa, T., Mohri, M., Tagawa, H., Egashira, K., Shimokawa, H., Kuga, T., Hirooka, Y., Takeshita, A. (April 1997). "Role of nitric oxide in substance P-induced vasodilation differs between the coronary and forearm circulation in humans". Journal of Cardiovascular Pharmacology. 29 (4): 546–553. doi:10.1097/00005344-199704000-00017. ISSN 0160-2446.
- ↑ Dionne, R. A., Max, M. B., Gordon, S. M., Parada, S., Sang, C., Gracely, R. H., Sethna, N. F., MacLean, D. B. (November 1998). "The substance P receptor antagonist CP-99,994 reduces acute postoperative pain*". Clinical Pharmacology & Therapeutics. 64 (5): 562–568. doi:10.1016/S0009-9236(98)90140-0. ISSN 0009-9236.
- ↑ Cerenia - Zoetis Inc.: Veterinary Package Insert
- ↑ Ratti, E., Carpenter, D. J., Zamuner, S., Fernandes, S., Squassante, L., Danker-Hopfe, H., Archer, G., Robertson, J., Alexander, R., Trist, D. G., Merlo-Pich, E. (1 December 2013). "Efficacy of Vestipitant, A Neurokinin-1 Receptor Antagonist, in Primary Insomnia". Sleep. 36 (12): 1823–1830. doi:10.5665/sleep.3208. ISSN 0161-8105.