Cannabinoid Receptor 2 Agonist Attenuates Pain Related Behavior in Rats with Chronic Alcohol/High Fat Diet Induced Pancreatitis

Abstract

BackgroundChronic 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.ResultsRats 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.ConclusionLY3038404 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.

Alcohol and high fat induced chronic pancreatitis: TRPV4 antagonist reduces hypersensitivity

“…4D). These results demonstrate that rats with AHF pancreatitis had less anxiety due to long term alcohol consumption, consistent with our previous published study (Zhang et al, 2014). …”

“…Consistent with our previous study (Zhang et al, 2014), the rats with AHF pancreatitis showed less fear behavior than did the normal chow control rats in light/dark box preference testing, i.e. they spent more time in the light chamber and had increased numbers of transitions between the light/dark chambers and increased exploratory activity (rearing events).…”

Genetically inducedvs.classical animal models of chronic pancreatitis: a critical comparison

“…Moreover, the rats showed visceral pain-like hypersensitivity evoked by mechanical and heat stimuli, suggesting altered nociception (15,47). In addition, histopathology and pain-related behavioral results correlated with each other (14). In this model, a potential role of autophagy in CP was also discovered because rats with CP induced by an alcohol diet and LPS injection showed decreased levels of LAMP2.…”

“…One of the oldest mechanisms for investigating the alcohol toxic effect in an experimental setting is feeding rodents with the Lieber-DeCarli diet, which involves supplementing liquid feed with ethanol (46). In recent studies (14,15), rats were fed a modified Lieber-DeCarli diet, that is, an alcohol and high-fat liquid diet, which resembles the nutrition of alcoholics. The rats developed a mild pancreatitis within 10-12 wk, presenting with acinar cell atrophy, fibrosis, vacuolization from fat deposition, and mild endocrine insufficiency from islet atrophy.…”

“…A number of excellent reviews (4)(5)(6)(8)(9)(10)(11) exist about animal models of CP; however, the mentioned, sine qua non pain syndrome is rarely addressed. Nociceptive, reflexive behaviors, such as mechanical or thermal sensitivity at the abdomen (12), and explorative behavior, investigated in the open field test (13), have been adopted as indicators of the pain state of mice and rats with CP (12,14,15). We have previously shown (16,17) that the severity of pain in patients with CP correlates with morphologic alterations in nerves, termed "neural plasticity," including enlarged nerves, increased nerve density, and infiltration of the perineurium by immune cells (pancreatic neuritis).…”