**8. Conclusion**

92 Pharmacology

In this study, cross-substitution between the discriminative effects of U-50,488H and TRK-820 was not observed. The agonists tested in this study, except E-2078, tended to substitute for the discriminative stimulus effects of U-50,488H rather than those of TRK-820. These results suggest that U-50,488H and TRK-820 have differential properties. Furthermore, noncompetitive NMDA antagonists phencyclidine (PCP, 0.5-2.0 mg/kg) and MK-801 (10-80 g/kg) dose-dependently generalized to the discriminative stimulus effects of U-50,488H (3.0 mg/kg, i.p.) in the cross-substitution tests. On the other hand, PCP and MK-801 at doses that generalized to the discriminative stimulus effects of U-50,488H did not generalize to those of TRK-820 (40 g/kg, i.p.) (Mori et al., 2006). The outcomes clearly indicate different

The effects of TRK-820 on hyperlocomotion and stereotyped behaviors (head-weaving, sniffing, and turning) induced by PCP were evaluated. These behaviors are thought to resemble the schizophrenia-like effects in humans. TRK-820 (10–100 g/kg, s.c.) dosedependently inhibited PCP (10 mg/kg, i.p.)-induced hyperlocomotion, and this effect was antagonized with nor-BNI (20 mg/kg, s.c.). PCP-induced stereotyped behaviors were also inhibited by treatment with TRK-820 in a dose-dependent manner. These findings that TRK-820 potentially ameliorates abnormal behaviors induced by PCP suggest its therapeutic

properties between TRK-820 and U-50,488H.

**7.1 The effect of TRK-820 on a rat model of schizophrenia** 

potential against the symptoms of schizophrenia (Yoshikawa et al., 2009).

parkinsonian patients with dyskinesia symptoms (Ikeda et al., 2009).

was inhibited by selective antagonist 5'-GNTI (Inan et al., 2009b).

vascular formation through the inhibition of cAMP/PKA signaling.

**7.3 The diuretic effect of TRK-820 in rats** 

**vasculature** 

**7.2 The effect of TRK-820 on dyskinesia symptoms in a parkinsonian rat model** 

The effects of TRK-820 on rotational behavior were investigated in unilateral 6 hydroxydopamine (6-OHDA)-treated rats (hemi-parkinsonian rats), and on dyskinesia produced by administering L-DOPA to hemi-parkinsonian rats for 3 weeks (dyskinesia rats). TRK-820 significantly ameliorated abnormal behavior in hemi-parkinsonian rats at 30 g/kg (s.c.), and L-DOPA induced dyskinesia at 10 and 30 g/kg (s.c.). This effect was antagonized by pretreatment with nor-BNI (20 mg/kg, s.c.). Additionally, co-administration of TRK-820 (3 and 10 μg/kg, s.c.) with L-DOPA for 3 weeks suppressed the development of L-DOPA-induced dyskinesia. TRK-820 may be a suitable drug for the treatment of

Diuresis is a well-recognized effect of conventional agonists in animals and humans. A diuretic effect of TRK-820 in rats has also been reported. TRK-820 (0.005-0.02 mg/kg, s.c.) dose-dependently induced a diuretic effect without developing tolerance, and this effect

The roles of the opioid system in vascular development were investigated (Yamamizu et al., 2011). U-50,488H and TRK-820 significantly inhibited endothelial cell differentiation and

**7.4 The effects of TRK-820 on endothelial cell differentiation and development of** 

**7. Other pharmacological effects** 

TRK-820 was a selective agonist. However, its pharmacological properties were different from those of conventional arylacetamide agonists, including U-50,488H. A noteworthy feature of TRK-820 was that it showed no preferential or aversive properties, whereas U-50,488H produced aversion. This disparity of properties between TRK-820 and arylacetamide agonists was reported to stem from the difference in receptor subtypes each compound interacted with: arylacetamide agonists would interact with 1 receptor subtype, whereas TRK-820 may interact with another receptor subtype (perhaps 3) (Endoh et al., 1999; 2000; 2001; Tsuji et al., 2000a; 2000b). Although opioid receptors have been classified historically into three types (, , and types) and further divided into several subtypes from the pharmacological viewpoint (Dhawan et al., 1996), only the three major types have been cloned (Satoh & Minami, 1995). Much evidence has been compiled indicating that various receptors, including opioid receptors, exist as homo- or hetero dimers of the receptors (George et al., 2000, 2002; Gomes et al., 2000, 2004; Devi, 2001; Levac et al., 2002; Wang, D et al., 2005), and receptor dimerization has been invoked to explain the discrepancy between widely varied pharmacologies and the identification of only three opioid receptor types. Therefore, the disparity of properties between TRK-820 and arylacetamide agonists may stem from the difference in receptor dimers each compound interacts with. Both TRK-820 and arylacetamide agonists are expected to be useful tools for the investigation of receptor dimerization and/or receptor subtype. As mentioned in section 2, a binding assay using [3H]TRK-820 and [3H]U-69,593 is thought to be a facile and useful method for achieving that purpose. However, [3H]TRK-820 is not currently available.

In addition to antipruritic and antinociceptive effects, TRK-820 exhibited various pharmacological effects, such as the treatment of the symptoms of schizophrenia or dyskinesia symptoms of parkisonian patients, or remedy for drug addiction. Moreover, TRK-820 has been already launched in Japan. TRK-820 is expected not only to be developed with the other indication, such as symptoms of schizophrenia or parkinson's disease, but also to be utilized to investigate pharmacology *via* the receptor.

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**5** 

*USA* 

*1Department of Anesthesiology,* 

**The Cannabinoid 1 Receptor and Progenitor** 

**Cells in the Adult Central Nervous System** 

Alexandra Sideris1, Thomas Blanck2 and Esperanza Recio-Pinto3

*2Department of Anesthesiology, Department of Physiology and Neuroscience* 

The aims of this chapter are to: (1) examine the key developments leading up to the discovery the cannabinoid 1 receptor (CB1R) and (2) assess the potential therapeutic benefits of cannabinoid drugs with respect to neurogenesis in the adult brain and spinal cord. As one of the most abundant G-protein coupled receptors found in the central nervous system, localization of CB1R and its role in the mature and in the developing brain will be discussed. Pharmacological studies with cannabinergic drugs, and studies utilizing knock-out mice of various endocannabinoid system components will be reviewed in the context of adult brain neurogenesis. The apparent conflicting data reveal the complexity of endocannabinoid signaling in this process. Though many studies have focused on CB1R and neurogenesis in the brain, none have evaluated the potential ability for CB1R to modulate the fate, and specifically neuronal differentiation, of adult spinal cord progenitors. The implications for CB1R modulation of adult neurogenesis are pivotal for understanding the behavioral and cognitive effects of chronic marijuana use, but also for assessing the potential consequences

The history leading up to the discovery of the "endocannabinoid (eCB) system" is an interesting one, sprouting from a decades- long quest for the active constituents of the marijuana plant, *Cannabis sativa*. Though the cannabis plant has long been used for a variety of purposes dating back more than 4000 years (O'Shaughnessy 1842; Mechoulam and Hanus 2000), only recently was it found that delta 9- tetrahydrocannabinol (Δ9-THC) was the ingredient responsible for the psychotropic effects associated and exploited with its use

One of the original and most ancient uses of the *Cannabis sativa* plant was to induce a trancelike state, often an essential component to the elaborate religious rites in ancient cultures ranging from the Chinese, to the Ayurvedic Indians, to the Persians and Greeks (O'Shaughnessy 1842; Aldrich 2006). Herodotus referred to the use of the hemp plant by the

of pharmacotherapeutics with CB1R agonists or antagonists

**2. Discovery of an endogenous cannabinoid system** 

(Mechoulam and Gaoni 1965).

**1. Introduction** 

*3Department of Anesthesiology; Department of Pharmacology New York University Langone Medical Center, New York* 

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