Noxious Noci's

What am I talking about? Nociceptors, which are the nerves that send pain signals from a distal site to the brain, and the stuff that sets them off (noxious stimuli). First, let's look at what nociceptive pain is:

"Nociceptive pain is caused when special nerve endings—called nociceptors—are irritated. Nociceptive pain is the type of pain you feel when you burn yourself, twist your ankle, or stub your toe. It is a dull or sharp aching pain, and it can be mild to severe. This type of pain can usually be controlled. Nociceptive pain can be a temporary condition, such as when you have a sprained ankle, but it can also be a chronic condition. Cancer pain and arthritis pain are common types of chronic nociceptive pain. Nociceptive pain usually responds well to pain medications, anti-inflammatory agents, or other drug therapies. It usually does not respond well to neurostimulation." http://www.poweroveryourpain.com/understand/chronic/paintypes

"Tissue damage or injury initiates signals that are transferred through peripheral nerves to the brain via the spinal cord. Pain signals are modulated throughout the pathways. This is how we become aware that something is hurting." http://www.medicinenet.com/pain_management/page2.htm

"Acute or nociceptive pain is part of a rapid warning relay instructing the motor neurons of the central nervous system to minimize detected physical harm. It is mediated by nocicepters, on A-δ and C fibers. These nociceptors are free nerve endings that terminate just below the skin, in tendons, joints, and in body organs. They serve to detect cutaneous pain, somatic pain and visceral pain. Nociception can be associated with nerve damage caused by trauma, diseases such as diabetes, shingles, irritable bowel syndrome, late-stage cancer or the toxic effects of chemotherapy. It typically responds well to treatment with opioids and NSAIDs. One of the challenges for researchers and clinicians alike is that chronic pain may involve a mix of both inflammatory and neuropathic components. In inflammatory nocicpetive pain, inflammation may cause damage to the neurons and produce neuropathic pain. Likewise, neuronal injury may cause an inflammatory reaction (neurogenic inflammation) that contributes to inflammatory pain." http://www.mdbiosciences.com/Portals/42723/docs/Nociception-Neuropathic-Inflammatory%20Pain.pdf

[For your own FYI, when you're trying to distinguish the type of pain:

"Neuropathic pain is caused by a malfunction of the nervous system due to an injury or an illness. Neuropathic pain can be a sharp, intense, shocking, or shooting pain. It is also very stubborn in that it does not usually respond as well as nociceptive pain to standard pain therapies, such as over-the-counter pain medications (for example, aspirin or ibuprofen) and prescription pain medications. Unlike nociceptive pain, neuropathic pain can often be managed by neurostimulation." http://www.poweroveryourpain.com/understand/chronic/paintypes ]

"Noxious stimuli and responses
There are three categories of noxious stimuli:

• mechanical (pressure, swelling, abscess, incision, tumour growth);
• thermal (burn, scald);
• chemical (excitatory neurotransmitter, toxic substance, ischaemia, infection).

The cause of stimulation may be internal, such as pressure exerted by a tumour or external, for example, a burn. This noxious stimulation causes a release of chemical mediators from the damaged cells including:

• prostaglandin;
• bradykinin;
• serotonin;
• substance P;
• potassium;
• histamine.

These chemical mediators activate and/or sensitise the nociceptors to the noxious stimuli." http://www.nursingtimes.net/nursing-practice/clinical-zones/pain-management/anatomy-and-physiology-of-pain/1860931.article

"Endometriotic implants cause a local inflammatory reaction which irritates nerve endings and sends noxious stimuli along the nerve pathways to the spinal cord and into the central nervous system (CNS) where they are interpreted as burning, dull, achy sensations or as sharp, stabbing, or crampy pains. The local inflammatory reaction is mediated by the increased production of substances, such as a variety of cytokines and prostaglandins, originating from the endometriotic implants and cells of the immune system. These substances also stimulate development of scarring and nodules around the endometriotic implants which may compress peripheral nerves compounding pain symptoms with signs of peripheral neuropathy. Pain symptoms are usually elicited when the nodules are compressed during pelvic examination or sexual intercourse. Endometriotic (chocolate) cysts may compress on other pelvic organs, causing pain and pressure during urination or bowel movements. If there is bleeding from the endometriotic lesions, as it frequently happens during the menstrual period, a woman may notice blood in the urine or stools or in secretions from other organs affected by endometriosis, e.g. blood in the sputum with endometriosis of the lungs. Because of increased systemic cytokine and prostaglandin production by the circulating immune cells, some women with endometriosis may experience generalized symptoms such as low-grade fever; crampy, generalized aches and pains; and nausea, vomiting, and diarrhea usually around the time of the menstrual period." http://www.endometriosisinstitute.com/endometriosis/management-of-pelvic-pain

The main event of this feature:

Primary Afferent Nociceptors and Visceral Pain

Victor Chaban

Charles R. Drew University of Medicine and Science and University of California, Los Angeles, USA

“Several lines of evidence indicated that there is a close relationship between nerve fiber density and endometriosis-associated pain. There is a significant increase in nerve fiber density in women with endometriosis who reported pelvic pain, suggesting these nerve fibers may play an important role in the mechanisms of pain generation.

One such mechanism may be the convergence of nociceptive stimuli and estrogen input on the primary afferent neurons which innervate viscera. Based on our results, it is likely that estrogen receptors (ERs) expressed in primary afferent neurons modulate nociceptive signaling. Our recent data suggest that estrogen acting on primary afferent nociceptors modulates the response to proand anti-nociceptive signals associated with the clinical presentation of functional disorders such as endometriosis.

The mechanism of endometriosis-induced nociceptive signaling is poorly understood and in some cases pain can be exacerbated by co-morbidity with other chronic pelvic pain syndromes such as irritable bowel syndrome, painful bladder syndrome, vulvodynia and fibromyalgia. It has also been shown that ectopic implants develop sensory nerve supply both in women and in animal models of endometriosis. Sensory input arriving from the visceral organ to the spinal cord divergences at the level of primary sensory neurons which further transmit considerable information from periphery to the central nervous system.

Several researchers have investigated the presence of nerve fibers in endometriotic lesions in both human and animal study. Using different types of specific immunohistochemical neuronal markers such as substance P (SP) and calcitonin gene related peptide (CGRP) sensory nerve fibers markers) in human peritoneal endometriotic lesions from women with visually and biopsy proven endometriosis, investigators have demonstrated multiple, small unmyelinated nerve fibers are present in peritoneal endometriotic lesions, and these peritoneal endometriotic lesions contain both Aδ and C nerve fibers. Accumulating evidence has shown these nerve fibers may play a critical role in pain production in patients with endometriosis, and a close histological relationship has been identified between these nerve fibers and endometriosis associated pain. Tulandi et al. (2001) reported that the distance between endometriotic glands and nerve fibers in endometriotic lesions from women with pain was closer than in women with no pain.

Endometriosis is an inflammatory disease, which is known to contain proinflammatory cytokines, prostaglandins, and other neuroactive agents that could readily activate the CGRP- and SP-positive C-fiber nociceptive afferents found in the endometriotic lesions. When these sensory nerve fibers are stimulated by inflammatory substances, neurotransmitters such as SP, CGRP can be secreted from sensory nerve endings. SP and CGRP can contribute to the inflammatory response by causing vasodilation, plasma extravasation and cellular infiltration by interacting with endothelial cells, arterioles, mast cells, neutrophils and immune cells. SP can also act on mast cells in the vicinity of sensory nerve endings to evoke de-granulation and the release of TNF-􀇂, histamine, prostaglandin D2 (PGD2) and leukotriene, providing a positive feedback. CGRP has a wide range of biological activities, including sensory transmission, regulation of glandular secretion, and inhibiting SP degradation by a specific endopeptidase to enhance SP release, thereby amplifying the effects.

Based on our preliminary results, it is likely that estrogen receptors (ERs) expressed in primary afferent neurons modulate chemical signaling associated with nociception. Nociception is a balance of pro- and anti-nociceptive inputs that is subject to regulation depending on the normal state of the organism. Sensitization of primary afferent neurons to stimulation may play a role in the enhanced perception of visceral sensation and pain. Chest pain from coronary heart disease, endometriosis, acute and recurrent/chronic pelvic pain in women or abdominal are all visceral pain sensations that may result in part from sensitization (Berkley et al. 2001; Mayer et al. 2001). Mechanisms of peripheral sensitization may involve increased transduction that is secondary to repeated stimulation or an increase in the excitability of the afferent nerves by molecules that decrease the excitation threshold (Zimmermann 2001).

These findings suggest that E2 may modulate sensory input at the primary afferent level. E2 can alter gene transcription, resulting in pro-nociceptive (reducing 􀇃-endorphin expression) or anti-nociceptive (increasing enkephalin expression) changes of endogenous opioid peptides , opioid receptors (Micevych and Sinchak 2001) and, by increasing levels of CCK, an anti-nociceptive and anti-opioid molecule (Micevych et al. 2002).

Our data support the idea that E2 modulates nociceptive responses in pelvic pain syndromes such as endometriosis, however, whether E2 is pro- or anti-nociceptive remains unresolved….Our data clearly showed the new role of nociceptors in pathophysiological aspects of chronic pelvic pain and potential way of designing future therapies.”

http://www.intechopen.com/download/get/type/pdfs/id/36770

"Neurotrophins (NTs), a family of neuronal growth factors, are overexpressed in endometriosis and encompass NGF, BDNF and NT-3 and NT-4/5. NT receptors, TrkA and p75NTR, and NT receptor-interacting proteins, MAGE and NDN, were also expressed. NTs and their receptors play a role in the development and maintenance of neural tissues in non-neuronal cell types such as endometriosis. Nerve fibers contain unmyelinated sensory C, myelinated sensory Adelta and adrenergic nerve fibers that innervate abnormal cell growths. An increased release of proinflammatory cytokines from endometriotic lesions is responsible for the excessive sensory innervation and development of chronic pelvic pain. The preponderance of the inflammatory milieu and subsequent hyperinnervation might be involved in the pathophysiology of pain generation in women with endometriosis." http://link.springer.com/article/10.1007/s00404-013-3049-8

"Calcium-binding proteins seem to be increased in endometriosis-associated nerve fibres and might play an important role in the chronic inflammatory condition and the pain pathogenesis of endometriosis." http://onlinelibrary.wiley.com/doi/10.1002/j.1532-2149.2013.00323.x/abstract;jsessionid=A4A598F96BBAA715C3121D4E3C8056D0.f02t02?deniedAccessCustomisedMessage=&userIsAuthenticated=false

"While increased levels of leptin have been reported in patients with endometriosis, their contribution to endometriosis pain has not been explored. Using a rodent model of endometriosis we provide evidence for an estrogen-dependent contribution of leptin in endometriosis-induced pain....This sensitivity to leptin is dependent on estrogen levels." http://www.sciencedirect.com/science/article/pii/S0306452213009482

"The exact aetiology of endometriosis is still not clear although a role for inflammation is increasingly accepted. We therefore investigated the inflammatory activity of eutopic tissue and that of the matching ectopic lesions from different locations by measuring the genetic expression of inflammatory chemokines and cytokines. The gene expression in matching eutopic and ectopic tissue was compared, as was the gene expression in lesions from different locations. A significantly higher mRNA expression of the chemokines ENA-78 and RANTES and the cytokines IL-6 and TNFα was observed in endometriotic lesions of the rectovaginal septum (RVS) compared to that of matching eutopic tissue. Comparisons across lesion locations showed a significantly higher expression of IL-6 and TNFα in the RVS compared to lesions from either the ovaries or the peritoneum. These results show that the production of some inflammatory chemokines and cytokines is significantly increased in the ectopic endometrial tissue compared to matching eutopic tissue. Furthermore, IL-6 and TNFα are produced in significantly higher quantities in RVS lesions compared to other lesions." http://www.hindawi.com/journals/mi/2013/450950/abs/

For more about estrogen receptors and endo, see http://endocomprehensive.blogspot.com/2013/11/estrogen-receptors-importance-in.html 

 

 

BONUS FEATURE:

We have talked before about the research into the connection between migraines and endo (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165129/  ,   http://www.ncbi.nlm.nih.gov/pubmed/22442736   ,  http://humrep.oxfordjournals.org/content/19/12/2927.full). Below is an article about the latest investigations into the cause of migraine pain and symptoms. Notice any similarities about  the neurons and neuro chemicals?

"Based on research, the best understanding we now have is that migraine arises from abnormally excitable neurons in the brain and trigeminal nerve. What causes the neurons to be abnormally excitable? Various things can do this, including low magnesium, abnormal calcium channels on the surface of the neuron, mitochondrial abnormalities, or other inherited brain chemical abnormalities. The newest things in the migraine story are the glia—the support cells in the brain—which also appear to have a role in transmitting pain, perhaps more so in chronic headache, although their story is still being determined....While there is still some controversy over the "vascular" part of migraine, the situation was recently summed up by Dr. Andrew Charles, UCLA migraine researcher. Dr. Charles indicated that while it is clear that vascular changes occur in migraine, it does not mean migraine is triggered by vascular processes, and that the dilation of blood vessels is neither necessary nor sufficient for causing migraine pain.

"According to existing trigeminovascular theory, once the messages come from the activated cells in the trigeminal nucleus in the brainstem, and travel to the trigeminal nerves that go to the dural blood vessels on the brain's surface, it causes dilation. However, the trigeminal activation also causes the release of brain chemicals called neuropeptides (substance P, CGRP or calcitonin gene-related peptide, neurokinin A, 5HT or serotonin, and noradrenalin).

"The release of these chemicals causes inflammation, and what is called peripheral sensitization. This is most likely what results in the throbbing pain most people experience. As the attack progresses, something can occur called central sensitization. When this occurs, it causes what is known as cutaneous allodynia. This means that things that are usually just a normal touch are now felt as painful. Many headache patients with allodynia cannot continue to wear earrings, necklaces or neckties, or their glasses. Some find that they cannot lie down on the side of the head pain, or report that "even their hair hurts." Up to 80% of migraine sufferers are affected by some degree of cutaneous allodynia, and it generally occurs in the late stages of a migraine attack when the pain is severe. This is why it is important to treat early when the pain is mild or moderate.

"When central sensitization becomes advanced, it can involve areas beyond the head, and simple touch on the arms or shoulder can be perceived as painful. For example, I am aware of one migraine sufferer who is bothered by the seams in her clothing during such an attack. At this stage of the migraine, migraine-specific medication is less likely to be helpful, and studies have shown that while they will reduce the pain and relieve the throbbing, they cannot abort the attack, and allodynic pain remains as well as other migraine symptoms. In late-stage migraine, other medications may be necessary in order to end the attack."  http://www.migrainesurvival.com/understand-migraine-pathophysiology-allodynia