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Azithromycin 1g orally in a single dose Treatment with cefuroxime axetil 1 g orally meets the cri- OR teria for minimum efcacy as an alternative regimen for uro- Doxycycline 100 mg orally twice a day for 7 days genital and rectal infection (95 order generic lady era menopause signs. Possible undertreatment of PID in female partners and possible missed opportunities to Patients diagnosed with uncomplicated gonorrhea who diagnose other STDs are of concern and have not been evalu- are treated with any of the recommended or alternative regi- ated in comparison with patient-delivered therapy and partner mens do not need a test-of-cure (i discount lady era 100 mg on line menopause hormone levels. Tis approach should not be considered a routine after completing therapy). Patients who have symptoms that partner management strategy in MSM because of the high risk persist after treatment should be evaluated by culture for for coexisting undiagnosed STDs or HIV infection. Persistent urethritis, cervicitis, Special Considerations or proctitis also might be caused by C. Most infections allergy and occur less frequently with third-generation cepha- result from reinfection rather than treatment failure, indicat- losporins (239). In those persons with a history of penicillin ing a need for improved patient education and referral of sex allergy, the use of cephalosporins should be contraindicated partners. Clinicians should advise patients with gonorrhea to only in those with a history of a severe reaction to penicillin be retested 3 months after treatment. Retesting losporin allergy, providers treating such patients should consult is distinct from test-of-cure to detect therapeutic failure, which infectious disease specialists. Azithromycin 2 g orally is efective is not recommended. Cephalosporin treatment following Efective clinical management of patients with treatable desensitization is impractical in most clinical settings. Patients Pregnancy should be instructed to refer their sex partners for evaluation As with other patients, pregnant women infected with N. Because spectinomycin is not available in the 60 days before onset of symptoms or diagnosis of infection in United States, azithromycin 2 g orally can be considered for the patient should be evaluated and treated for N. Resistance Use of this approach (68,71) should always be accompanied by Suspected treatment failure has been reported among per- eforts to educate partners about symptoms and to encourage sons receiving oral and injectable cephalosporins (300–304). For male patients informing Terefore, clinicians of patients with suspected treatment fail- female partners, educational materials should include informa- ure or persons infected with a strain found to demonstrate in tion about the importance of seeking medical evaluation for vitro resistance should consult an infectious disease specialist, conduct culture and susceptibility testing of relevant clinical Vol. No treatment fail- Gonococcal Conjunctivitis ures have been reported with the recommended regimens. In the only published study of the treatment of gonococ- cal conjunctivitis among U. Gonococcal infection frequently is asymptomatic in sex partners of patients who have DGI. As with uncomplicated Recommended Regimen gonococcal infections, patients should be instructed to refer Ceftriaxone 1 g IM in a single dose their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners). Consider lavage of the infected eye with saline solution once. Gonococcal Meningitis and Endocarditis Persons treated for gonococcal conjunctivitis should be treated presumptively for concurrent C. Recommended Regimen Ceftriaxone 1–2 g IV every 12 hours Management of Sex Partners Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infections, Terapy for meningitis should be continued for 10–14 Management of Sex Partners). Treatment of complicated DGI should be undertaken Disseminated Gonococcal Infection (DGI) in consultation with an infectious disease specialist. DGI frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthri- Management of Sex Partners tis. Te infection is complicated occasionally by perihepatitis Patients should be instructed to refer their sex partners and rarely by endocarditis or meningitis. Some strains of for evaluation and treatment (see Gonococcal Infection, N. No recent studies have been published on the treatment of DGI. Gonococcal Infections Among Infants Treatment Gonococcal infection among infants usually is caused by Hospitalization is recommended for initial therapy, espe- exposure to infected cervical exudate at birth. It is usually an cially for patients who might not comply with treatment, acute illness that manifests 2–5 days after birth. Te preva- for those in whom diagnosis is uncertain, and for those lence of infection among infants depends on the prevalence of who have purulent synovial efusions or other complica- infection among pregnant women, whether pregnant women tions. Examination for clinical evidence of endocarditis and are screened for gonorrhea, and whether newborns receive meningitis should be performed. Te most severe manifestations of should be treated presumptively for concurrent C. Less severe manifestations include rhinitis, vaginitis, urethritis, Recommended Regimen and reinfection at sites of fetal monitoring. Ceftriaxone 1 g IM or IV every 24 hours ophthalmia neonatorum Caused by N. Gonococcal oph- newborns thalmia is strongly suspected when intracellular gram-negative Sepsis, arthritis, and meningitis (or any combination of diplococci are identifed in conjunctival exudate, justifying these conditions) are rare complications of neonatal gonococcal presumptive treatment for gonorrhea after appropriate cultures infection. Localized gonococcal infection of the scalp can result for N. Appropriate chlamydial test- from fetal monitoring through scalp electrodes. Presumptive treatment gonococcal infection in neonates who have sepsis, arthritis, for N. Specimens obtained from increased WBCs (but not gonococci) in a Gram-stained smear the conjunctiva, vagina, oropharynx, and rectum that are cul- of conjunctival exudate. Positive Gram-stained smears of exudate, CSF, or joint susceptibility before a defnitive diagnosis is made. A defni- aspirate provide a presumptive basis for initiating treatment tive diagnosis is vital because of the public health and social for N. Diagnoses based on Gram-stained smears consequences of a diagnosis of gonorrhea. Nongonococcal or presumptive identifcation of cultures should be confrmed causes of neonatal ophthalmia include Moraxella catarrhalis with defnitive tests on culture isolates. Ceftriaxone 25–50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10–14 days, if meningitis is documented Recommended Regimen OR Ceftriaxone 25–50 mg/kg IV or IM in a single dose, not to exceed Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration 125 mg of 10–14 days, if meningitis is documented Topical antibiotic therapy alone is inadequate and is unnec- essary if systemic treatment is administered. Prophylactic Treatment for Infants Whose Mothers Have Gonococcal Infection other Management Considerations Infants born to mothers who have untreated gonorrhea are Simultaneous infection with C. Both mother and infant should be tested for chlamydial infec- Recommended Regimen in the Absence of Signs of Gonococcal Infection tion at the same time that gonorrhea testing is conducted (see Ophthalmia Neonatorum Caused by C. Ceftriaxone 25–50 mg/kg IV or IM, not to exceed 125 mg, in a single dose Ceftriaxone should be administered cautiously to hyperbiliru- binemic infants, especially those born prematurely. Follow-Up other Management Considerations Infants who have gonococcal ophthalmia should be hospi- Both mother and infant should be tested for chlamydial talized and evaluated for signs of disseminated infection (e.

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The best image is tracked by moving the transducer along the course of the iliac crest in the direction of the ASIS (Figure 4 cheap lady era 100mg on-line women's health clinic eagle river alaska. When positioning the transducer buy lady era american express menstruation related disorders, the three muscular layers of the abdominal wall will be seen on the screen. The iliac bone will be seen at one side of the screen as black. On the other side of the screen, deeper, the abdominal cavity and eventually peritoneum or the bowel may be seen. The three abdominal muscles, the EOM, the IOM and the TAM, are seen as hypo-echoic longitudinal bands (Figure 4. The muscular fascias between them are seen as hyper-echoic and hyper-lucent. Along the fascia between the IOM and the TAM, two oval structures 50 | Ultrasound Blocks for the Anterior Abdominal Wall may be seen corresponding to the IHN and IIN. The needle is inserted with an in-plane approach, parallel and aligned to the long axis of the transducer. The in-plane approach would possibly decrease the risk of advancing the needle into the peritoneal cavity. Always control for blood vessels and aspirate before injecting. Ultrasounds have been shown to decrease local anesthetic volume and improve the success of the block (Willschke 2005, Willschke 2006, Eichenberger 2009). The main disadvantages are the cost of equipment and the need for adequate training of 4. Iliohypogastric and Ilioinguinal Nerve Block | 51 anesthesiologists before clinical application of ultrasound-guided blocks. Anesthesiologists need to develop a good understanding of the anatomical structures involved in the blocks. They need to acquire both a solid knowledge in ultrasound technology and the practical skills to visualize nerve structures. Since IHN and IIN visualization is not always possible because it is operator, patient and equipment dependent, the TAM plane near the ASIS may be a more useful landmark (Ford 2009). A good endpoint for the inexperienced practitioner of ultrasound-guided IIB may be the plane between the TAM and the IOM where the nerves are reported to be found in 100% of cases (Ford 2009). It is important to note that IHN and IIN can not always be reliably identified; this is not a simple block! Ultrasound novices starting to perform IIB should scan the 52 | Ultrasound Blocks for the Anterior Abdominal Wall region at least 14–15 times before performing the block using the muscle planes as an endpoint (Ford 2009). Importantly, the block should be performed above the ASIS. In conclusion, since a lower local anesthetic volume is required for IIB at the ASIS level, selective block of these nerves instead of classical TAPB is advised (Figure 4. Genitofemoral Nerve Block Zhirajr Mokini Occasionally, the inguinal field block (IFB)/local infiltration anesthesia (LIA) (see the detailed discussion in Chapter 7) seem to fail due to pain experienced during spermatic cord manipulation. In these cases, ideally, a block of the genital branch of genitofemoral nerve (gGFB) should be performed because local anesthetic infiltration into the inguinal canal improves the efficacy of the block (Yndgaard 1994). A selective gGFB is not possible except under direct intraoperative vision (Rab 2001). The IIN and gGFN generally enter the deep inguinal ring and run together into the inguinal canal on the surface of the spermatic cord. In all cases the gGFN innervates the cremaster muscle (Rab 2001). The blind landmark for the inguinal canal that corresponds to the underlying spermatic cord is the point on the skin, one finger-breadth above the mid-point between the ASIS and the mid-penopubic fold at the symphysis pubis (Hsu 2005). The typical injection site for the gGFB is referred to be superior-lateral to the pubic tubercle in order to inject the anesthetic near the spermatic cord (Peng 2008). Caution should be taken because at the pubis level the inferior epigastric vessels are found respectively at 7. Since it is not possible to achieve gGFN visualization with ultrasounds, the technique includes the injection of the local anesthetic inside and outside the spermatic cord (Peng 2008). The transducer is aligned to visualize the femoral artery in the long axis and then is moved upwards towards the inguinal ligament where the femoral artery becomes the external iliac artery. The spermatic cord is seen superficially to the external iliac artery just opposite to the internal inguinal ring. It appears as an oval or circular structure with 1 or 2 arteries (the testicular artery and the artery to the vas deferens) and the vas deferens as a tubular structure within it (Peng 2008). The transducer is moved medially away from the femoral artery and an out-of-plane technique is used. The final position is about 2 finger-breadths to the side of the pubic tubercle and perpendicular to the inguinal line. While with this technique the spermatic cord is likely to be found outside the inguinal canal, anesthetic infiltration into the inguinal canal may provide a greater probability of blocking not only the gGFN, but also the IIN and/or the IHN endings (Rab 2001). Inguinal canal injection would be suitable for inguinal surgery both in the case of local, general or spinal anesthesia. An ultrasound-guided gGFB with a 10-18 mHz transducer can be performed. The transducer is placed under the inguinal ligament at the intersection between the hemiclavear line and the line between the pubic tubercle and the ASIS (Figure 5. The femoral artery is visualized transversely along the short axis (Figure 5. Subsequently, the transducer is moved medially towards the pubic tubercle. The inguinal canal can be seen between the femoral artery and the pubic bone. It is located more superficial under the aponeurosis of the EOM as an oval shadow containing the 5. Genitofemoral Nerve Block | 55 spermatic cord in it. It is useful to ask the patient to cough in order to see tissue movement of the spermatic cord. A 10-20 ml of anesthetic is injected into the inguinal canal just after the needle penetrates the EOM aponeurosis (Figure 5. A “pop” is also felt while the needle penetrates the aponeurosis. The spread of the anesthetic will block the gGFN and/or the IIN and IHN. Intracanalar tissues will be hydro-dissected and may be observed as gelatinous during surgery at the dissection of the aponeurosis of the EOM (Figure 5. The two images of the procedure described in Figure 5. If a stimulated needle is used, visible testicle retraction and twitching of the cremaster muscle may be occasionally present. Since the gGFN runs together with the cremasteric vessels ensheathed by the cremasteric fascia, needle aspiration is mandatory (Rab 2001).

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PTH rP was initially described as 1 141 PTH-like peptide N C the causative circulating factor in the (mw 16 order lady era 100 mg visa pregnancy jokes cartoons,000) hum oral hypercalcem ia of m alignancy buy lady era 100 mg visa women's health and mental health, par- ticularly in breast cancer, squam ous cell cancers of the lung, renal cell cancer, and -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 other tum ors. It is now clear that PTH rP can be expressed not only in cancer but PTH LYS ARG SER VAL SER GLU ILE GLN LEU M ET HIS ASN LEU GLY LYS also in m any norm al tissues. It m ay play an PTH-like peptide LYS ARG ALA VAL SER GLU HIS GLN LEU LEU HIS ASP LYS GLY LYS im portant role in the regulation of sm ooth m uscle tone, transepithelial Ca transport (eg, in the m am m ary gland), and the differ- entiation of tissue and organ developm ent [7,13]. N ote the high degree of hom ology between PTH rP and PTH at the am ino end of the polypeptides. M W — m olecular weight; N — am ino term inal; C— carboxy term inal. The CaSR is a guanosine increases CaSR-Ca binding, which activates the G-protein. The G- triphosphate (GTP) or G-protein–coupled polypeptide receptor. CaSR also can be found in thyroidal C cells, brain cells, and es PTH secretion, and increases PTH degradation. The CaSR allows Ca to act as a first is an integral part of Ca hom eostasis within the kidney. The gene m essenger on target tissues and then act by way of other second- for CaSR is located on hum an chrom osom e 3q13 [3,4,7,14–16]. W ithin parathyroid cells, hypercalcem ia term inal. The norm al recom m ended dietary intake of Ca for an adult is 800 to 1200 m g/d (20–30 m m ol/d). Foods high in Ca content include m ilk, Gastrointestinal dairy products, m eat, fish with bones, oysters, and m any leafy absorption of dietary calcium (Ca) green vegetables (eg, spinach and collard greens). Although serum Ca levels can be m aintained in the norm al range by bone resorp- Net Ca absorption % of intake tion, dietary intake is the only source by which the body can Site mmol/d mg/d absorbed replenish stores of Ca in bone. Ca is absorbed alm ost exclusively within the duodenum , jejunum , and ileum. Each of these intesti- Stomach 0 0 0 nal segm ents has a high absorptive capacity for Ca, with their Duodenum 0. Approxim ately 400 m g of the usual 1000 m g dietary Ca intake is absorbed by the intestine, and Ca loss by way of intesti- Colon 0 0 0 nal secretions is approxim ately 200 m g/d. Therefore, a net absorption of Ca is approxim ately 200 m g/d (20% ). Biliary and Total* 5 200 20 pancreatic secretions are extrem ely rich in Ca. FIGURE 5-12 Lumen Proposed pathways for calcium (Ca) absorption across the intestinal Ca2+ Ca2+ Ca2+ Ca2+ epithelium. Two routes exist for the absorption of Ca across the 1 2 3 4 intestinal epithelium: the paracellular pathway and the transcellular M icrovilli route. The paracellular pathway is passive, and it is the predominant means of Ca absorption when the luminal concentration of Ca is high. This is a nonsaturable pathway and can account for one half to two thirds of total intestinal Ca absorption. The paracellular absorp- Actin tive route may be indirectly influenced by 1,25-dihydroxy-vitamin D3 M yosin-I (1,25(OH)2D3) because it may be capable of altering the structure of intercellular tight junctions by way of activation of protein kinase C, Calmodulin making the tight junction more permeable to the movement of Ca. However, 1,25(OH)2D3 primarily controls the active absorption of Ca. Ca2+ Calbindin-Ca -3 complex Because the intestinal concentration of Ca usually is 10 mol and the Free intracellular Ca concentration is 10-6 mol, a large concentration gra- Ca2+ Calbindin- dient favors the passive movement of Ca. Ca is rapidly and reversibly M icro- diffusion synthesis vesicular bound to the calmodulin-actin-myosin I complex. Ca may then move transport to the basolateral area of the cell by way of microvesicular transport, Calcitriol or ionized Ca may diffuse to this area of the cell. This decrease in Na/Ca Ca2+-ATPase Ca concentration again favors the movement of Ca into the microvil- exchange 2+ 2+ Ca Ca lae. As the calbindin-Ca complex dissociates, the free intracellular Ca Lamina propria is actively extruded from the cell by either the Ca-adenosine triphos- phatase (ATPase) or Na-Ca exchanger. Calcitriol may also increase the synthesis of the plasma membrane Ca-ATPase, thereby aiding in the active extrusion of Ca into the lamina propria [2,7,9,17,18]. Total serum Ca consists of arteriole arteriole ionized, protein bound, and com plexed fractions (47. The com plexed Ca is bound to m olecules such as phosphate and citrate. The ultrafilterable Ca equals the total of the ionized and com plexed fractions. Ca2+ Ca2+ Alkalosis decreases the ionized Ca [1,6,7]. Ca is filtered at the glom erulus, and 1,25(OH)2D3 colocalized here with the ultrafilterable fraction (UFCa) of plasm a Ca entering the Calcitonin proxim al tubule (PT). W ithin the proxim al convoluted tubule Thiazides (PCT) and the proxim al straight tubule (PST), isosm otic reabsorp- CNT tion of Ca occurs such that at the end of the PST the UFCa to TFCa ratio is about 1. Passive paracellular pathways account for about 80% of Ca reabsorption in this segm ent of the nephron, with the PCT rem aining 20% dependent on active transcellular Ca m ovem ent. Cortex CTAL N o reabsorption of Ca occurs within the thin segm ent of the loop of H enle. Ca is reabsorbed in sm all am ounts within the m edullary segm ent of the thick ascending lim b (M AL) of the loop of H enle M edulla M AL and calcitonin (CT) stim ulates Ca reabsorption here. H owever, the cortical segm ents (cTAL) reabsorb about 20% of the initially fil- tered load of Ca. Under norm al conditions, m ost of the Ca reab- Papilla sorption in the cTAL is passive and paracellular, owing to the favorable electrochem ical gradient. Active transcellular Ca trans- port can be stim ulated by both parathyroid horm one (PTH ) and 1,25-dihydroxy-vitam in D3 (1,25(O H )2D3) in the cTAL. In the early distal convoluted tubule (DCT), thiazide-activated Ca trans- port occurs. The DCT is the prim ary site in the nephron at which Ca reabsorption is regulated by PTH and 1,25(O H )2D3. Active 100 PT DT Urine transcellular Ca transport m ust account for Ca reabsorption in the 100 DCT, because the transepithelial voltage becom es negative, which would not favor passive m ovem ent of Ca out of the tubular lum en. ATPase— adenosine triphosphatase; CaBP-D— Ca- 40 (40) binding protein D; DT— distal tubule; VDR— vitam in D receptor. The G-protein also increases 2+ G-protein + ↑Ca IP3 activity of phospholipase A2 (PLA ), which increases the concen- K 2 1 A – PK-C tration of arachidonic acid (AA).

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Readministration of a marijuana cigarette cific cognitive deficits and relating these effects directly to or oral 9-THC alleviated the objective and subjective ef- marijuana use order generic lady era menopause the musical chicago. Whereas THC appears to produce its great- fects effective lady era 100mg women's health on birth control, a finding suggesting the establishment of a withdrawal est decrement in free recall or short-term memory, it has symptom. Similar findings were reported by Georgotas and Chapter 106: Marijuana 1521 Zeidenberg in abstinent subjects who had smoked high More recently, Budney et al. One study juana users seeking treatment for marijuana dependence had (14) found that lower doses of THC (80 and 120 mg/day, experienced symptoms consistent with either moderate or orally, each for 4 days) initially produced ratings of 'high,' severe dependence (23). These investigators also reported increased food intake over baseline by 35% to 45%, and that marijuana-dependent persons exhibit substantial prob- decreased verbal interaction among participants (14). Comparison of marijuana- and cocaine-depen- ance developed to the subjective effects of THC but not to dent patients revealed comparable substance-use histories its effects on food intake or social behavior. Abstinence from and a range of impairments in both groups. However, the THC produced anxious, depressed, and irritable symptoms, marijuana-dependent patients showed less severe depen- decreased the quantity and quality of sleep, and decreased dence. The marijuana group was more ambivalent and less food intake (14). A similar study conducted with marijuana confident about stopping their marijuana use than the co- cigarettes resulted in similar effects and led to the conclusion caine group was about stopping their cocaine use. The au- that abstinence symptoms may play a role in maintaining thors concluded that treatment-seeking, marijuana-depen- daily marijuana use, even at levels of use that do not produce dent persons exhibit substantial problems and urged tolerance (15). There are numerous cases in which Some predisposing factors may contribute to marijuana persons seek treatment for dependence of which marijuana dependence in some persons. These patients typically com- juveniles diagnosed with both substance abuse and conduct plained of being unable to stop or to decrease their mari- disorders have serious problems related to cannabis, and juana use despite experiencing sleepiness, depression, inabil- most met standard adult criteria for cannabis dependence ity to concentrate, and memorization difficulties that they (25). Two-thirds of these cannabis-dependent patients re- directly attributed to marijuana exposure. The data indicate that for adolescents ies reported similar problems in daily users of marijuana with conduct problems, cannabis use is not benign. Several groups of investigators have used DSM-III-R risk factors may also contribute. With regard to prevalence of marijuana abuse and use, abuse, and dependence as defined by DSM-IV criteria dependence, the strongest evidence was provided by the (26). These investigators concluded that in women, genetic Epidemiological Catchment Area study involving 20,000 risk factors have a moderate impact on the probability of persons in five geographic areas of the United States (21). By contrast, marijuana abuse or dependence, and three-fifths of these the family and social environment substantially influences met the criteria for dependence. After an extensive review risk of ever using cannabis but plays little role in the proba- of the literature, Hall et al. Early attempts to demonstrate spontaneous with- Kandel and Davies estimated that the risk of dependence drawal after cessation of chronic marijuana or THC treat- in near-daily marijuana users was one in three (17). Factors that have been associated with marijuana depen- The physical withdrawal syndrome for cannabinoids and dence include poor academic achievement, deviant behav- opioids in rodents shares many of the same characteristics. It ior, rebelliousness, maladjustment, difficult parental rela- is also clear that, in humans, THC is an essential reinforcing tions, early initiation of drug use, and family history of drug component in marijuana (31). The major complaints by marijuana-dependent per- abused by humans, it has been difficult to train animals to sons are loss of control over drug use, cognitive and motiva- self-administer cannabinoids. Although the physical charac- tional impairments, lowered self-esteem, depression, and teristics of cannabinoids probably contribute to this diffi- spousal discord. The risk of cannabis abuse and dependence culty, the general opinion persists that cannabinoids lack was found to increase with the frequency of smoking occa- rewarding effects and therefore are devoid of dependence sions and slightly decreased with age (22). Virtually all striatal projection neurons contain CB1 warding and aversive effects, depending on the concentra- mRNA, which is also expressed in putative GABAergic in- tion used. It may well be that these dual properties have terneurons that enable functional interactions between the hindered the development of a THC model of self-adminis- direct and indirect striatal output pathways (41). Nevertheless, these studies clearly demonstrate that mRNA is found in striatonigral neurons that contain dynor- cannabinoid self-administration is not confined to humans. The presence of CB1 receptors in sensory (42) and auto- Cannabinoid Receptors nomic peripheral fibers (43,44) has been reported. CB1 re- It is now widely recognized that most of the neurobehavioral ceptors seem to be mostly restricted to spinal interneurons, and peripheral actions of marijuana and THC result from rather than at the axonal level (45), thus possibly accounting activation of selective receptors, two of which, named CB1 for spinal mechanisms of pain control ascribed to psycho- and CB2, have been cloned and characterized (33,34). However, indirect evidence also exists development of transgenic mice lacking the genes encoding for the presence of CB1 receptors in peripheral sensory affer- for either of these two receptors, the CB1 and CB2-receptor ents (46), a finding thus supporting the concept that canna- knockout mice (35–37), have provided conclusive evidence binoids may also exert analgesia at the peripheral level. The that the effects of THC on motor behavior, body tempera- presence of CB1 receptors in parasympathetic and sympa- ture, cardiovascular function, and nociception, on the one thetic fibers, on the other hand, may be at the basis of hand, and on some immunologic responses, on the other the vascular and smooth muscle–relaxing activity of THC hand, are mediated by CB1 and CB2 receptors, respectively. There is no evidence for the pres- malian tissues and have been found not only in the central ence of CB2 receptors in the central nervous system, except and peripheral nervous systems, but also in both male and for their expression in microglia. Clearly, given that CB2 female reproductive organs, immune cells, the gastrointesti- receptors seem to be mostly confined to cells of the immune nal tract, the liver, and the heart (38). In the central nervous system (34), it would not be surprising to find these proteins system, CB1 receptors are most abundant in the hippocam- only in those central nervous system cells deputed to im- pus (i. Lower density of CB1 receptors is present Studies have revealed that activation of the subunits of G /i in discrete nuclei of other brain regions such as the hypo- Go proteins, with subsequent inhibition of adenylate cyclase thalamus, brainstem, thalamus, and limbic forebrain, thus through both CB1 and CB2 receptors (47), blockade of volt- possibly accounting for THC activity on body temperature, age-activated calcium (Ca2 ) channels of the N- and P/Q- appetite, supraspinal mechanisms of pain perception, sen- type through CB1 receptors (48), and activation of inwardly sory perception, and mood or reward. CB1 receptors are rectifying potassium channels through CB1 receptors (49), associated with nerve fibers and axon terminals, but not may not be the sole intracellular signaling messages deliv- in the neuronal soma. This pattern is consistent with the ered by psychoactive cannabinoids. There is now evidence presynaptic inhibitory effects of cannabinoids on neuro- for the coupling of CB1, but not CB2 receptors, to Gs pro- transmitter release in the brain (see ref. CB1- teins, with consequent activation of adenylyl cyclase. It is expressing cells in mouse forebrain can be divided into dis- not clear yet whether this effect may explain the biphasic tinct neuronal subpopulations. Most of the cells that highly nature of cannabinoid effects on behavior in several tests. In the hippocampus, amygdala, and entorhinal cortex THC and synthetic and endogenous cannabinoids can area, CB1 mRNA is present at low but significant levels either stimulate (50) or inhibit (51) NO formation. The in many non-GABAergic cells that can be considered as former effect results in inhibition of dopamine release from projecting principal neurons. These data are in good agree- invertebrate ganglia, whereas the inhibition of NO release ment with the observation that cannabinoids act on princi- in granule cerebellar cells seems to result from inhibition pal glutamatergic circuits as well as modulate local GABAer- of voltage-activated Ca2 channels. In any case, modulation gic inhibitory circuits by inhibiting glutamate and GABA of NO levels may result in changes in cyclic guanosine Chapter 106: Marijuana 1523 monophosphate intracellular concentrations. Finally, pro- sients in HL60 cells through these receptors. Interestingly, tein phosphorylation catalyzed by mitogen-activated pro- in this study, AEA was shown to be a very weak and partial tein kinase is coupled to both CB1- and CB2-receptor stimu- agonist at CB2 receptors. This intracellular effect, together with agonist at CB2 receptors, AEA, and much more so its meta- inhibition of the cyclic adenosine monophosphate bolically stable analogues (R)-methanandamide and 2′-flu- (cAMP)–dependent protein kinase A, is at the basis of can- oro-2-methyl-arachidonoyl-ethanolamide, act as relatively nabinoid action on the expression of several genes such as potent (Ki between 12 and 100 nM) and selective CB1- krox-24 in HL60 cells (52) or the prolactin receptor and receptor agonists, and thus can be considered useful phar- the high-affinity receptors trk for the nerve growth factor in macologic tools for studies on the bioactivity of endocan- human breast cancer cells (53).