scholarly journals Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy

2015 ◽  
Vol 113 (5) ◽  
pp. 1501-1510 ◽  
Author(s):  
Megan L. Uhelski ◽  
Iryna A. Khasabova ◽  
Donald A. Simone
Keyword(s):  
Peripheral Neuropathy ◽  
Spontaneous Activity ◽  
Mechanical Response ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Mechanical Stimuli ◽  
Painful Neuropathy ◽  
Platinum Based Chemotherapy ◽  
C Fiber

Painful neuropathy frequently develops as a consequence of commonly used chemotherapy agents for cancer treatment and is often a dose-limiting side effect. Currently available analgesic treatments are often ineffective on pain induced by neurotoxicity. Although peripheral administration of cannabinoids, endocannabinoids, and inhibitors of endocannabinoid hydrolysis has been effective in reducing hyperalgesia in models of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy (CIPN), few studies have examined cannabinoid effects on responses of nociceptors in vivo. In this study we determined whether inhibition of fatty acid amide hydrolase (FAAH), which slows the breakdown of the endocannabinoid anandamide (AEA), reduced sensitization of nociceptors produced by chemotherapy. Over the course of a week of daily treatments, mice treated with the platinum-based chemotherapy agent cisplatin developed robust mechanical allodynia that coincided with sensitization of cutaneous C-fiber nociceptors as indicated by the development of spontaneous activity and increased responses to mechanical stimulation. Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds, and decreased evoked responses to mechanical stimuli. Cotreatment with CB1 (AM281) or CB2 (AM630) receptor antagonists showed that the effect of URB597 was mediated primarily by CB1 receptors. These changes following URB597 were associated with an increase in the endocannabinoid anandamide in the skin. Our results suggest that enhanced signaling in the peripheral endocannabinoid system could be utilized to reduce nociceptor sensitization and pain associated with CIPN.

scholarly journals A Second Generation of Carbamate-Based Fatty Acid Amide Hydrolase Inhibitors with Improved Activity in vivo

ChemMedChem ◽  
2009 ◽  
Vol 4 (9) ◽  
pp. 1505-1513 ◽  
Author(s):  
Jason R. Clapper ◽  
Federica Vacondio ◽  
Alvin R. King ◽  
Andrea Duranti ◽  
Andrea Tontini ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Second Generation ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark B. Wiley ◽  
Pedro A. Perez ◽  
Donovan A. Argueta ◽  
Bryant Avalos ◽  
Courtney P. Wood ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
The Body ◽  
Mucosal Tissues ◽  
Degradative Enzymes ◽  
Health And Disease ◽  
Amide Hydrolase

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl-sn-glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe in vivo pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.

Warm-Sensitive Afferent Splanchnic C-Fiber Units In Vitro

1997 ◽  
Vol 77 (6) ◽  
pp. 2989-3002 ◽  
Author(s):  
David W. Adelson ◽  
Jen Yu Wei ◽  
Lawrence Kruger
Keyword(s):  
Receptive Fields ◽  
Sense Organ ◽  
Cardiovascular Responses ◽  
Peak Temperature ◽  
Mechanical Stimuli ◽  
Tonic Component ◽  
Brown Adipose ◽  
C Fiber

Adelson, David W., Jen Yu Wei, and Lawrence Kruger. Warm-sensitive afferent splanchnic C-fiber units in vitro. J. Neurophysiol. 77: 2989–3002, 1997. Receptive fields of 41 slowly conducting sensory fibers were located using a thermal (warm) search stimulus in an in vitro splanchnic nerve-mesentery preparation. Warm-sensitive receptive fields were punctate and were densest in the region surrounding the prevertebral ganglia, an area with prominent deposits of brown adipose tissue, where the abdominal aorta branches into the major trunks supplying the abdominal viscera. Impulse activity was recorded while applying a warm stimulus to identified receptive fields (RFs). The warm stimulus consisted of a warming ramp (10–15°C in 1–2 s to a 42–49°C peak temperature) followed by a 10- to 30-s period during which the RF was maintained at this peak temperature (plateau phase). Eighty percent (33/41) of warm-sensitive units responded to warming with discharge comprising both a phasic and a tonic component (slowly adapting warm-sensitive, or SA-W, units). The remainder (8/41) responded with only phasic discharge (rapidly adapting warm-sensitive, or RA-W, units). Units' adaptation characteristics were consistent from trial to trial and when applying stimuli from different positions. Fifty percent of SA-W units (8/16) and 17% of RA-W units (1/6) were activated by transient exposure to 9–90 nM bradykinin (BK). Twenty-seven percent (9/33) of SA-W units and 12%(1/8) of RA-W units were activated by probing their RF with von Frey hairs with bending forces <10 mN (∼1 g equivalent mass). An additional five SA-W units tested were activated by strong mechanical stimuli (compression with a metal probe or firm stretching). No BK-responsive warm-sensitive units were activated by von Frey probing <10 mN, but two (both SA-W) responded to strong mechanical stimuli. In six SA-W units and one RA-W unit, the number of impulses evoked by warming ∼5 min after exposure to BK was >2 SD greater than the mean pre-BK response, indicating sensitization. This sensitization was transient, the response to warming returning to within one standard deviation of the pretrial mean or less over the course of the next 5–10 min. Changes in background activity, mechanical sensitivity, BK sensitivity, and BK-induced sensitization were noted in various splanchnic units over the course of prolonged observations, suggesting that these indices may not reliably distinguish unit type, but instead may indicate the functional state of the sense organ. Splanchnic neurons responsive to the intense warming used in the present in vitro experiments may participate in the cardiovascular responses observed in vivo in heat-stressed rats. The dense distribution of warm-receptive fields in the vicinity of the celiac-superior mesenteric ganglionic complex is consistent with the localization of splanchnic thermosensitive units previously noted in vivo in the rabbit.

Characterization of Aδ- and C-Fibers Innervating the Plantar Rat Hindpaw One Day After an Incision

2002 ◽  
Vol 87 (2) ◽  
pp. 721-731 ◽  
Author(s):  
Esther M. Pogatzki ◽  
G. F. Gebhart ◽  
Timothy J. Brennan
Keyword(s):  
Spontaneous Activity ◽  
Mechanical Response ◽  
Tissue Injury ◽  
Mechanical Stimulus ◽  
Response Threshold ◽  
Mechanical Stimuli ◽  
Median Response ◽  
Sham Procedure ◽  
C Fibers ◽  
Afferent Fibers

Primary hyperalgesia after tissue injury is suggested to result from sensitization of primary afferent fibers, but sensitization to mechanical stimuli has been difficult to demonstrate. In the companion study, sensitization of mechano-responsive Aδ- and C-fibers did not explain pain behaviors 45 min after an incision in the rat hindpaw. In the present study, we examined mechanical response properties of Aδ- and C-fibers innervating the glabrous skin of the plantar hindpaw in rats 1 day after an incision or sham procedure. In behavioral experiments, median withdrawal thresholds to von Frey filaments were reduced from 522 mN before to 61 mN 2 and 20 h after incision; median withdrawal thresholds after sham procedure were stable (522 mN). Responses to a nonpunctate mechanical stimulus were increased after incision. In neurophysiological experiments in these same rats, 67 single afferent fibers were characterized from the left tibial nerve 1 day after sham procedure ( n = 39) or incision ( n = 28); electrical stimulation was used as the search stimulus to identify a representative population of Aδ- and C-fibers. In the incision group, 11 fibers (39%) had spontaneous activity with frequencies ranging from 0.03 to 39.3 imp/s; none were present in the sham group. The median response threshold of Aδ-fibers was less in the incision (56 mN, n = 13) compared with sham (251 mN, n = 26) group, mainly because the proportion of mechanically insensitive afferents (MIAs) was less (8 vs. 54% after sham procedure). Median C-fiber response thresholds were similar in incised (28 mN, n = 15) and sham rats (56 mN, n = 13). Responsiveness to monofilaments was significantly enhanced in Aδ-fibers 1 day after incision; stimulus response functions of C-fibers after incision and after sham procedure did not differ significantly. Only Aδ-fibers but not C-fibers sensitized to the nonpunctate mechanical stimulus. The size of receptive fields was increased in Aδ- and C-fibers 1 day after incision. The results indicate that sensitization of Aδ- and C-fibers is apparent 1 day after incision. Because sensitization of afferent fibers to mechanical stimuli correlated with behavioral results, sensitization may contribute to the reduced withdrawal threshold after incision. Spontaneous activity in Aδ- and C-fibers may account for nonevoked pain behavior and may also contribute to mechanical hyperalgesia by amplifying responses centrally.

scholarly journals Blocking of Fatty Acid Amide Hydrolase Activity with PF-04457845 in Human Brain: A Positron Emission Tomography Study with the Novel Radioligand [11C]CURB

2015 ◽  
Vol 35 (11) ◽  
pp. 1827-1835 ◽  
Author(s):  
Isabelle Boileau ◽  
Pablo M Rusjan ◽  
Belinda Williams ◽  
Esmaeil Mansouri ◽  
Romina Mizrahi ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Fatty Acid ◽  
Human Brain ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Emission Tomography ◽  
Positron Emission ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Positron emission tomography with [11C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test–retest reliability of [11C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test–retest [11C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n = 2 each). The composite parameter γ k3 (an index of FAAH activity, γ = K1/ k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [11C]CURB injection. Oral administration of PF-04457845 reduced [11C]CURB binding to a homogeneous level at all three doses, with γ k3 values decreased by ≥91%. Excellent reproducibility and good reliability (test–retest variability = 9%; intraclass correlation coefficient = 0.79) were observed across all regions of interest investigated. Our findings suggest that γ k3/[11C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.

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