Substance P: Difference between revisions

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 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>

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 | http://www.nature.com/nature/journal/v405/n6783/full/405180a0.html</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.