Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis.
BACKGROUND
Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet.


RESULTS
Rats fed the AHF diet developed visceral pain-like behaviors detectable by week 3 and reached a maximum at week 5 that persists as long as the diet is maintained. Rats with AHF induced chronic pancreatitis were treated with LY3038404 HCl (10 mg/kg, orally, twice a day for 9 days). The treated animals demonstrated significantly alleviated pain related behaviors after 3 days of dosing, including increased paw withdrawal thresholds (PWT), prolonged abdominal withdrawal latencies (ABWL), and decreased nocifensive responses to noxious 44°C hotplate stimuli. Terminal histological analysis of pancreatic tissue sections from the AHF chronic pancreatitis animals demonstrated extensive injury, including a global pancreatic gland degeneration (cellular atrophy), vacuolization (fat deposition), and fibrosis. After the LY3038404 HCl treatment, pancreatic tissue was significantly protected from severe damage and fibrosis. LY3038404 HCl affected neither open field exploratory behaviors nor dark/light box preferences as measures of higher brain and motor functions.


CONCLUSIONS
LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management.
Liping
L
Zhang
Robert H
RH
Kline
Terry A
TA
McNearney
Michael P
MP
Johnson
Department of Physiology, MS-508 College of Medicine, University of Kentucky, 40526-0298 Lexington, KY, USA. kwhigh2@uky.edu.
Karin N
KN
Westlund
D000438:Alcohols / Q000633:toxicity; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003623:Dark Adaptation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D017288:Pain Threshold / Q000187:drug effects; D050500:Pancreatitis, Chronic / Q000150:complications* / Q000209:etiology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D012720:Severity of Illness Index; D059265:Visceral Pain / Q000188:drug therapy* / Q000209:etiology*
D000438:Alcohols; D063386:Cannabinoid Receptor Agonists; D043884:Receptor, Cannabinoid, CB1