In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB 1 ) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid [anandamide and 2-arachidonoylglycerol (2-AG)] levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 [cyclohexylcarbamic acid-3Ј-carbamoyl-biphenyl-3-yl ester] on 1) nociception in the "plantar test" and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5-2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB 1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and (R)-(ϩ)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN55,212-2 (4 nmol)] also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB 1 receptors and only CB 1 receptors, respectively. The TRPV1-mediated antinociception and CB 1 -mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB 1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25-100 nmol) also caused CB 1 -mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB 1 or TRPV1 receptors in healthy rats.Two G-protein-coupled receptors for Cannabis psychotropic component ⌬ 9 -tetrahydrocannabinol have been cloned to date (Matsuda et al., 1990;Munro et al., 1993) and are implicated in the control of nociception under both physiological and pathological conditions (for review, see IversenThis work was partly supported by the VolkswagenStiftung (to V.D.M.) and Progretti di Ricerca di Rilevante Interesse Nazionale 2003 (Ministero dell'Istruzione dell'Università e della Ricerca, Rome, Italy) (to S.M.).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.093286.ABBREVIATIONS: CB 1 , cannabinoid receptor type 1; CB 2 , cannabinoid receptor type 2; ACSF, artificial cerebrospinal fluid; 2-AG, 2-arachidonoylglycerol; FAAH, fatty acid amide hydrolase; % MPE, percentage of the maximal possible effect; PAG, periaqueductal gray; RVM, rostral ventromedial medulla; TRPV1, transient receptor potential vanilloid type-1; ca...

Background-Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases; however, they have profound consequences on the structure and function of the heart, which over time cause a cardiomyopathy that leads to congestive heart failure. Methods and Results-Administration of doxorubicin in rats led to a dilated myopathy, heart failure, and death. To test whether the effects of doxorubicin on cardiac anatomy and function were mediated by alterations in cardiac progenitor cells (CPCs), these cells were exposed to the anthracycline, which increased the formation of reactive oxygen species and caused increases in DNA damage, expression of p53, telomere attrition, and apoptosis. Additionally, doxorubicin resulted in cell-cycle arrest at the G2/M transition, which led to a significant decrease in CPC growth. Doxorubicin elicited multiple molecular adaptations; the massive apoptotic death that occurred in CPCs in the presence of anthracycline imposed on the surviving CPC pool the activation of several pathways aimed at preservation of the primitive state, cell division, lineage differentiation, and repair of damaged DNA. To establish whether delivery of syngeneic progenitor cells opposed the progression of doxorubicin cardiotoxicity, enhanced green fluorescent protein-labeled CPCs were injected in the failing myocardium; this treatment promoted regeneration of cardiomyocytes and vascular structures, which improved ventricular performance and rate of animal survival. Conclusions-Our results raise the possibility that autologous CPCs can be obtained before antineoplastic drugs are given to cancer patients and subsequently administered to individuals who are particularly sensitive to the cardiotoxicity of these agents for prevention or management of heart failure. (Circulation. 2010;121:276-292.)

The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.