5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadols putative inhibition of GABAA receptors at high doses (significant inhibition at 100 μM). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadols ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels. In accordance, the 5-HT3 receptor antagonist ondansetron can be used to treat tramadol-associated nausea and vomiting. Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor. Pharmacokinetics
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys.
The differences in travel time from the epicenter to the observatory are a measure of the distance and can be used to image both sources of earthquakes and structures within the Earth. Also, the depth of the hypocenter can be computed roughly. P-wave speed
Upper crust soils and unconsolidated sediments: 2–3 km (1.2–1.9 mi) per second
Upper crust solid rock: 3–6 km (1.9–3.7 mi) per second
Lower crust: 6–7 km (3.7–4.3 mi) per second
Deep mantle: 13 km (8.1 mi) per second. S-waves speed
Light sediments: 2–3 km (1.2–1.9 mi) per second in
Earths crust:4–5 km (2.5–3.1 mi) per second
Deep mantle: 7 km (4.3 mi) per second

Seismic wave arrival
As a consequence, the first waves of a distant earthquake arrive at an observatory via the Earths mantle. On average, the kilometer distance to the earthquake is the number of seconds between the P- and S-wave times 8. Slight deviations are caused by inhomogeneities of subsurface structure. By such analysis of seismograms, the Earths core was located in 1913 by Beno Gutenberg. S-waves and later arriving surface waves do most of the damage compared to P-waves. P-waves squeeze and expand the material in the same direction they are traveling, whereas S-waves shake the ground up and down and back and forth. Earthquake location and reporting
Earthquakes are not only categorized by their magnitude but also by the place where they occur. The world is divided into 754 Flinn–Engdahl regions (F-E regions), which are based on political and geographical boundaries as well as seismic activity.