We do not understand the reasons for this discrepancy, but possible explanations include the weak antinociceptive activity of oleylethanolamide or small changes in rearing conditions, which may strongly affect behavioral responses in mice. Local and systemic administration of palmitylethanolamide alleviated pain behaviors elicited by a diverse group of chemical irritants, which included formalin, acetic acid, kaolin and magnesium sulfate. In all cases, treatment with the cannabinoid CB receptor antagonist SR144528 2 Žbut not of the cannabinoid CB receptor antagonist 1 . SR141716A prevented the effects of palmitylethanolamide, indicating that a common mechanism may be involved in these responses. Such broad antinociceptive properties strengthen the hypothesis that palmitylethanolamide may play a key role in the intrinsic control of pain initiation. Moreover, these properties support the notion that the putative receptor activated by palmitylethanolamide may provide a useful target for analgesic drug Ž development Calignano et al., 1998, 2000; Piomelli et al., . 2000 . Further support to this proposal comes from the fact that palmitylethanolamide may exert both analgesic Ž . Calignano et al., 1998; Jaggar et al., 1998; present study Ž and anti-inflammatory effects Benvenuti et al., 1968; Facci . et al., 1995; Mazzari et al., 1996 . Thus, drugs aimed at the putative palmitylethanolamide receptor might offer the advantage of combining these two complementary therapeutic properties. Additional experiments are needed, however, to unequivocally establish whether the analgesic and anti-inflammatory actions of palmitylethanolamide are mediated by the same putative receptor blocked by SR144528. Despite its ability to attenuate a variety of phasic pain responses,pipp racks such as those elicited by formalin and magnesium sulfate, palmitylethanolamide had no effect on capsaicin-induced nocifensive behavior.

Capsaicin, the active principle in chili pepper, is thought to produce pain by selectively activating VR1-type vanilloid receptors on pe- Ž ripheral sensory fibers Caterina et al., 1997; Szallasi and . Blumberg, 1999; Davis et al., 2000 . Accordingly, the fact that palmitylethanolamide did not inhibit capsaicin-induced pain at doses that completely prevented other nociceptive responses suggests that palmitylethanolamide does not directly interfere with nociceptor-mediated pain transmission. In keeping with this possibility, palmityl- Ž ethanolamide had no effect on thermal nociception Table . 1 , which is also thought to require phasic nociceptor Ž . activation Besson and Chaouch, 1987 . By contrast, and in agreement with the presence of cannabinoid CB recep- 1 Ž . tors in sensory neurons Hohmann and Herkenham, 1999 , we report here that anandamide inhibits capsaicin nociception. Moreover, in previous studies, we have shown that anandamide prevents thermal nociception and that this effect is also blocked by the cannabinoid CB antagonist 1 Ž . SR141716A Beltramo et al., 1997 . A plausible explanation for our findings is that anandamide and palmitylethanolamide exert their peripheral antinociceptive effects by interacting with different molecular and cellular targets. According to this hypothesis, anandamide may activate cannabinoid CB receptors located on capsaicin-sensitive 1 primary afferents, resulting in the decreased responsiveness of these afferents to noxious stimuli. Palmitylethanolamide, on the other hand, may stimulate an uncharacterized receptor, blocked by SR144528 and located on non-neuronal peripheral cells or capsaic in-insensitive neurons. The existence of distinct molecular and cellular targets for anandamide and palmitylethanolamide might also account for the synergistic effects displayed by these compounds on formalin-evoked or kaolin-evoked nocicep-tion. Whether or not these speculations turn out to be correct, the analgesic properties of palmitylethanolamide and anandamide underscore the important functions served by these lipid messengers in pain signaling, and the potential interest of the A 19-year-old female was brought to the emergency department by emergency medical services with complaints of generalized weakness, an inability to move her extremities, and near syncope. The patient stated that she began feeling generalized weakness that morning, which she initially attributed to her “sleeping position.” Over the day the weakness worsened, culminating in difficulty or inability to move her extremities and a near syncopal episode.

The patient stated she had attempted to stand up from a seated position when she “felt like [she] was going to pass out.” The patient called 911 for assistance. On further discussion, the patient revealed she had experienced one similar episode of weakness earlier in the year, but this had resolved spontaneously and was not as severe. She does not have a primary care physician and she had never sought care for this complaint. The patient said she noticed generalized abdominal pain, nausea, and constipation, associated with each of these episodes of weakness and light headedness. She denied any recent illnesses. She stated she treats her bipolar disorder with daily cannabis and consumes alcohol daily as well. University of Maryland Medical Center, Department of Emergency Medicine, Baltimore, Maryland University of Maryland School of Medicine, Department of Emergency Medicine, Baltimore, Maryland University of Maryland School of Medicine, Department of Epidemiology and Public Health, Baltimore, Maryland.The patient had a history of anxiety, depression, migraines, and normocytic anemia. Surgical history included an adenoidectomy and tonsillectomy as a child. She had no pertinent family history. Her social history included daily alcohol use, drinking a total of 1.75 liters of vodka over a two-week period. She started smoking when she was 16 years old, smoking a pack per day, but quit a year prior to presentation. The patient smoked cannabis daily. Her only medication was ferrous sulfate 325 milligrams daily. She had no known drug or environmental allergies. On physical exam, the patient was alert and in no acute distress but appeared tired. She was able to stand unassisted. At the time of triage, she was afebrile , her heart rate was 40 beats per minute, she was breathing 20 times per minute, her blood pressure was 115/90 millimeters of mercury, and she had an oxygen saturation of 98% on room air. She weighed 77.3 kilograms and was 1.65 meters tall . She was well developed, well nourished and speaking in complete sentences without accessory muscle use. She was oriented as to person, place and time. She was without sensory deficits and had normal muscle tone. Her strength was 4/5 with elbow flexion and extension, hand grip, knee flexion and extension, and ankle dorsi- and plantar-flexion bilaterally. Deep tendon reflexes were 2+ for the bilateral brachioradialis and patellar reflexes.

No clonus could be provoked. She did not have any cranial nerve defects, and she had a normal gait and station. She had normal range of motion of all four extremities, and she did not have any edema. Her lower extremity compartments were soft in both the thighs and the lower legs bilaterally. She exhibited tenderness around her bilateral shoulders and shins. Her head was normocephalic and without signs of injury. Her oropharynx was clear and moist, and her pupils were equal, round, and reactive to light. Her conjunctiva and extraocular motions were normal. Her neck was supple and had a full range of motion, without jugular venous distention or adenopathy. On cardiovascular exam the patient was bradycardic with a regular rhythm, and she had a normal S1/S2 without gallops, friction rubs, or murmurs. On auscultation her breath sounds were clear without wheezes, rales or rhonchi. Her abdomen was non-distended, soft and non-tender throughout with normal bowel sounds. Her skin was warm and dry, and her capillary refill was less than two seconds. She did not have any rashes. Her mood, affect, and behavior were normal. The patient’s electrocardiogram is shown . The results of the patient’s initial laboratory evaluation are shown in Table 1. A test was ordered, and a diagnosis was made.This case involved a young woman with episodic weakness. She reported near syncope, transient extremity paralysis, and generalized weakness. She reported associated nausea, abdominal pain, and constipation. She also reported regular substance use in the form of marijuana and alcohol. Her review of systems was otherwise unremarkable, and notably it was negative for recent illness or gastrointestinal distress outside of this episode. With this in mind, I began to formulate a differential diagnosis. Episodic weakness, particularly extremity paralysis,rack of clones suggests metabolic and electrolyte derangements such as hypokalemic periodic paralysis. Weakness may also suggest a primary neurologic condition, including Guillain-Barré syndrome, multiple sclerosis, and other demyelinating disorders. The patient’s near syncope may be due to orthostatic hypotension or neurocardiogenic causes. Her GI symptoms could be due to a broad array of abdominal conditions, but her substance use suggests these symptoms may be related to an ingestion. The patient’s bradycardia could be due to disseminated Lyme disease, myocarditis, or other etiologies of heart block. More information is required. I used the information provided by her physical exam to further refine my differential diagnosis. Her physical exam was notable for a tired-appearing female with bradycardia. Pertinent negative findings included that the compartments of the legs were noted to be soft, clinically excluding a compartment syndrome. Additionally, the patient had no focal neurologic deficits based on the documented neurologic exam. Several findings, including cerebellar signs were not documented, but the patient was noted to have normal gait and station. Further, the case did not provide any imaging studies – notably, there was no neuroimaging included.

The patient’s ECG showed a sinus bradycardia with sinus arrhythmia, short QTc with T-wave inversions in aVR and V1, and U waves, but it did not show a heart block. I then reviewed the patient’s laboratory findings. She was noted to have a mild anemia, elevated creatine kinase with myoglobinuria, hematuria, proteinuria, and urinary findings consistent with a urinary tract infection. Additionally, she has multiple electrolyte derangements, including hypokalemia, hyperchloremia with acidosis, hypermagnesemia and hypophosphatemia. She had an elevated creatinine and a mild transaminitis. These laboratory findings suggest her symptoms are due to a metabolic derangement. This patient had a non-anion gap metabolic acidosis. The differential diagnosis for non-anion gap metabolic acidosis includes diarrhea, intestinal fistulae, renal tubular acidosis , ureteroileostomy, ureterosigmoidostomy, toluene use, ketoacidosis, D-lactic acidosis, and administration of chloriderich solutions. After cross-referencing this with the case details, some of these diagnoses can be eliminated based on the history, exam, and review of systems. Specifically, the patient reported constipation, thereby eliminating diarrhea as a cause. She also had no surgical history, hence eliminating ureteroileostomy and ureterosigmoidostomy as causes. Although her diet is not mentioned, there is no reported history of abnormal ingestion of food or fluids; so I reasonably eliminated chloride-rich solution ingestion as a cause. This left proximal and distal RTA, toluene use, ketoacidosis, and D-lactic acidosis as diagnoses under consideration. When cross-referencing these with the case details and laboratory findings once again, some options were not consistent with the presentation. Specifically, there was no ketonuria making ketoacidosis unlikely. Lactic acidosis is a result of a hypoperfusion state, and the clinical case did not provide any evidence of hypoperfusion making this unlikely as well. There were some additional laboratory findings outside of the metabolic panel that needed to be considered. Namely, the patient’s hemoglobin and hematocrit were slightly abnormal . Also, she had an elevated creatine kinase and myoglobin as well as slight elevation in her aspartate transaminase. Her urine also showed some hematuria, pyuria, and proteinuria as well as findings of nitrites and leukocyte esterase. When these labs are considered in conjunction with the metabolic abnormalities, my differential diagnosis now included hypokalemic periodic paralysis, rhabdomyolysis, adrenal insufficiency, proximal and distal RTA, inflammatory myopathy, and poisoning . Adrenal insufficiency can cause metabolic derangements and presents with symptoms including fatigue, weight loss, GI complaints, and myalgias, and may also include psychiatric symptoms. In primary adrenal insufficiency, the potassium is high and sodium is low, which is not consistent with this case. In secondary or tertiary adrenal insufficiency, potassium is normal or low, sodium can be high or low, and chloride is normal with a low glucose.These are not consistent with the findings in this case either; so I eliminated adrenal insufficiency from my differential diagnosis. Inflammatory myopathies present with muscle weakness, cardiac involvement, and laboratory findings including elevated serum creatinine kinase and elevated myoglobin levels in both urine and serum. These patients usually present with acute onset of “antisynthetase syndrome,” constitutional symptoms, Raynaud’s phenomenon, and a nonerosive arthritis.While the laboratory findings here were consistent with a possible myopathy, the clinical presentation was not classic, making this a less likely possibility. Another consideration was rhabdomyolysis potentially resulting from compartment syndrome. Compartment syndrome occurs from increased fascial compartment pressure with subsequent tissue hypoperfusion, which can lead to muscle necrosis and rhabdomyolysis.