Example Of Monoamines In Nociception

p.483 The cell bodies of primary-order neurons or pain-transmitting neurons reside in the dorsal root ganglia just lateral to the spine along the sensory pathways that penetrate the posterior part of the cord. The second order neurons are found in the dorsal horn (p.484) Most nociceptive information tranvels by means of ascending columns in the lateral spinothalamic tract (also called the anterolateral funiculus). The principal target for nociceptive afferents is the thalamus (the major relay station of sensory information in general) Third order neurons project to portions of the CNS involved in the processing and interpretation of pain, the chief areas being the reticular and limbic systems and cerebral cortex. (p 484)

The cerebral cortex directs functions like speech, behavior, reactions, movement, thinking, and learning. In fact, some research suggests that bipolar disorder originates with problems with the thalamus, which links sensory input to good and bad feelings. The hippocampus also affects depression. It, like the amygdala, is part of the limbic system. It is vital in processing long-term memory. This section of the brain registers recurring fear. In people with clinical depression, the hippocampus is much smaller. Research suggests, even, that ongoing exposure to stress impairs the growth of nerve cells in this part of the brain. One of the most important jobs of the brain is to process senses, through neurons. Neurotransmitters are specific substances that help relay information to the brain. Scientists have identified many neurotransmitters that affect depression. A lack or excess of the neurotransmitters acetylcholine, serotonin, norepinephrine, dopamine, glutamate, lithium carbonate and gamma-aminobutyric acid are thought to contribute to depression. Acetylcholine is involved in learning and enhances memory. Serotonin helps regulate sleep, appetite, and mood, and inhibits pain. Research shows the idea that many depressed people have reduced levels of serotonin. Low levels of a byproduct of serotonin have been linked to a high risk for suicide. Norepinephrine is a neurotransmitter which constricts blood vessels and raises blood pressure. An excess in

Major depressive disorder is one of the most common mental disorders, with a 12-month prevalence of 6.7% of adults in the United States (NIMH). There is no definite etiology of depression, but several risk factors have been identified. Functional and structural changes in the brain have also been explored. The most common treatment for depression is the use of drugs that act on monoamine transmitters, including norepinephrine, dopamine, and serotonin. Decreases in these transmitters, especially serotonin, were hypothesized to play an important role in the cause of depression (Breedlove & Watson, 2013). The serotonin hypothesis led to the development of selective-serotonin reuptake inhibitors (SSRIs), which increase the amount of serotonin in the brain. Further research suggests that the serotonin hypothesis is not entirely accurate and the neurobiology of depression is much more complex. The “chemical imbalance” explanation of depression may not reflect the full range of causes and may be given greater credibility by patients and doctors than is supported by evidence based research.

The availability of prescription painkillers has increased substantially, painkillers are drugs that deal with the nervous system, it blocks pain and the patient will feel a “high”. The most common prescribed drugs

which in turn inhibits the second order neurons that transmit the nociceptive signals to the

ERα has been shown to be expressed in dynorphin neurons in the dorsal horn of the spinal cord and directly modulates dynorphin release, which in turn regulates DORs (Gintzler & Liu, 2012). Dynorphin release is often associated with nociception and has been linked to opioid-induced hyperalgesia (Vanderah, Ossipov, Lai, Malan, & Porreca, 2001). Interestingly, dynorphin and KOR activation is also linked to significant analgesia, particularly in women (Gear et al., 1996). Estrogens upregulate KORs in both intact and ovariectomized female rats in a dose-dependent manner (Lawson, Nag, Thompson, & Mokha, 2010). This apparent contradiction can be explained by spinally synthesized estrogen mediating KOR/MOR heterodimerization in the dorsal horn, which switches dynorphin from being pronociceptive to antinociceptive (N. J. Liu, Chakrabarti, Schnell, Wessendorf, & Gintzler, 2011). In areas outside of the spinal cord, mechanisms involving ERα modulating dynorphin release vary by brain location, and also depend on whether or not ERE-dependent pathways are activated (Gottsch et al., 2009).

As mentioned above, opioids are extremely helpful in killing acute and cancer pain. Because opioid receptors are G-protein coupled reactions, the inhibitory G-protein is usually coupled or attached with the receptors (Ghelardini et al., 2015, page 219). The onset of reaction in inhibit the pain is rapid and effective due to multiple inhibitory actions at the terminal site (refer to the previous section of mechanism of action). Besides, the interaction of opioids gradually increases the threshold of pain neuron as well as attenuates the pain subjective evaluation (Ghelardini et al., 2015, page 220).

Opioids are pain relievers that bind to opioid receptors on nerve cells throughout the body. They produce feelings of euphoria, tranquility and sedation. However, opioids are “considered the most harmful of all illicit drugs” (Amato et al., 2005, p.321).

Chemically related and interact with opioid receptors on nerve cells in the body and brain

The opioids produce analgesic effects no matter is endogenous or synthetic, including morphine, codeine and methadone. (3)Endogenous opioid peptides such as endorphins, enkephalins and dynorphins activate opioid receptors including mu-receptors (mainly), delta-receptors, kappa-receptors and ORL1 receptors to produce different effects. One of the non-analgesic effects is the disruption of sleep-wake behaviour by the opioids’ actions on the ventrolateral preoptic nucleus (VLPO). The differences of the pharmacokinetic properties between the 3 opioids mentioned and the possible mechanisms of sleep-wake regulations will be discussed below.

Opioid receptors are members of the G-protein-coupled receptors (GPCRs) family, which consists of 7 transmembrane domains linked together by 3 extracellular and 3 intracellular loops (Trescot et al., 2008). The three different classes of opioid receptors are: -opioid receptor, -opioid receptor and -opioid receptor, which are distributed throughout the central and peripheral nervous systems (Trescot et al., 2008). -opioid receptors are associated with analgesia, euphoria and physical dependence and are predominately located in the brainstem and thalamus (Trescot et al., 2008). -opioid receptors, on the other hand, are primarily found in limbic brain topography, brain stem and spinal cord, and are related to dysphoria and analgesia (Trescot et al., 2008). Although -opioid receptor mechanisms are poorly understood, it has been indicated to also have psychomimetic effects (Trescot et al., 2008).

Other hormonal imbalances contribute to depression: (a) low thyroid levels, (b) low human growth hormone, (c) low prolactin levels (Kaplan and Sadock 532). Additionally, structural changes in the brain and brain functioning are linked to MDD. According to Kaplan Sadock, the greatest “consistent abnormality observed in the depressive disorders is increased frequency of abnormal hyperintensities in subcortical regions, such as periventricular regions, the basal ganglia, the thalamus… Some depressed patients also may have reduced hippocampal or caudate nucleus volumes, or both, suggesting more focal defects in relevant neurobehavioral systems. Diffuse focal areas of atrophy

Chronic Neuropathic Pain after Spinal Cord Injury: Spinal cord injury (SCI) affects up to 500,000 people every year around the world (Singh et al., 2014) with devastating physical, psychological and social consequences. SCI not only damages motor systems, it also directly affects sensory systems, causing chronic, debilitating neuropathic pain. The incidence of neuropathic pain after SCI is extremely high, with at least half and up to 90% of SCI individuals experiencing neuropathic pain, described as paroxysmal pain that can be continuous and may be evoked by any sensory stimulus, not necessarily painful. Current pharmacological interventions offer minimal, transient relief to a minority (30%) of sufferers of SCI-induced neuropathic pain (Cousins, 2012). Current treatment strategies utilize conventional drugs for chronic pain, which only address pain symptomatically and cannot provide lasting relief or prevent relapse of symptoms, leading to drug dependency and further reducing quality of life for SCI patients. Due to the myriad events that take place after SCI, delineating the causes of neuropathic pain development is difficult. Neuropathic pain in general, and more so in SCI, has an inherent degeneracy in mechanisms, which is likely why targeted pharmacological treatment approaches often fail to provide significant relief.

An increase in endogenous opioids can act upon the ON/OFF cells in the RVM, which can in effect turn “off” the pain signal, or dampen it dramatically, hence the use of opioids as pain killers. Proving the presence of opioids within the placebo mechanism was determined by using an opioid antagonist naloxone3, which was able to reduce the placebo effect if there were strong expectation cues, but not as effectively when the expectation

5-HT receptor agonists demonstrate a wide range of clinical treatment targets ranging from depression to therapeutics for migraines and headaches. With an abundance of 5-HT receptor categories and subtypes, the following provides an insight into several drugs and their action on the respective subtypes: