The most important finding of this study is that activation of cannabinoid receptors is beneficial against abdominal pain as well as disease pathology of cerulein-induced acute pancreatitis. Pain management is a key cornerstone in the conventional therapy of acute pancreatitis and still represents a major clinical challenge. In-sufficient pain control results in high respiratory rates, reduced lung function, and inadequate ingestion, factors that significantly delay recovery and may worsen the course of the disease.1,2
The use of opioids as a standard therapy regimen is effective but frequently results in severe and difficult-to-handle side effects, such as nausea, vomiting, decreased gastrointestinal motility, and adynamia, which overlap with the symptoms of pancreatitis.2
Nonsteroidal analgesics lack these side effects but do not provide adequate pain relief. We demonstrate here that a cannabinoid completely blocked abdominal pain in a state of cerulein-induced acute pancreatitis. Importantly, this beneficial effect was elicited following systemic delivery of HU210 at a low dose lacking central side effects, suggesting that HU210 abolished pancreatitis-induced abdominal pain via peripheral mechanisms. Consistent with this appraisal, we could demonstrate that cannabinoid-induced analgesia was not accompanied by effects such as hindrance of activity, motor dysfunction, sedation, or catalepsy, which are typically associated with activation of cannabinoid receptors in the central nervous system.
Because lower-abdominal tactile hypersensitivity after pancreatic inflammation essentially represents secondary hyperalgesia and allodynia (phenomena that require sensitization of central synapses), the antinociceptive effects we observed likely occur as a result of cannabinoid-induced decrease in nociceptor excitability and consequently, reduced central sensitization. Consistent with peripheral antinociceptive effects of cannabinoids, CB1 localized on peripheral nociceptive endings has been shown to negatively modulate excitability of nociceptors and inhibit release of peptides,18
thereby countering neurogenic inflammation. Interestingly, neurogenic inflammation has been postulated to be a key mechanism in the pathophysiology of acute pancreatitis.19
In addition to CB1, we also observed a CB2-component to the antinociceptive effects of HU210 in cerulein-induced pancreatitis. Although a functional contribution of CB2 expressed on nerves is possible, the anti-inflammatory effects of CB2 could also indirectly account for its antinociceptive role. Our anatomical data from human specimens reveal the presence and up-regulation of both CB1 and CB2 in neural, as well as non-neural cells in the pancreas. Future studies are therefore required to pinpoint the precise loci and mechanisms of cannabinoid-induced anti-nociception in acute pancreatitis.
Another key feature of acute pancreatitis is local inflammation resulting from acinar cell injury, which, if significant and unchecked, can lead to a systemic inflammatory response syndrome, thereby initiating a potentially fatal stage of the disease.20
The probable benefits of anti-inflammatory therapies in acute pancreatitis have been hypothesized previously.20
In this study, we found that a low dose of HU210, which is devoid of central side effects, does exert moderate anti-inflammatory effects in the pancreas and partially reduces cerulein-induced disease pathology. This finding is consistent with a recent study11
demonstrating that HU210 exerts local anti-inflammatory effects in a model of experimental colitis in mice, suggesting that cannabinoids are generally beneficial in visceral inflammatory disorders. Whereas CB1 receptors were found to play a key role in the study by Massa et al, we observed that the moderate anti-inflammatory effects achieved via low-dose HU210 in acute pancreatitis largely require both CB1 and CB2 activation. Another interesting aspect of the present study is the finding that anandamide as well as cannabinoid receptors are up-regulated in human pancreatitis. We observed that blockade of CB1 and CB2 led to a significant worsening of pancreatitis-induced pain but produced only a nonsignificant trend toward exacerbation of cerulein-induced disease pathology. These data suggest that in our experimental conditions, an induction of the endocannabinoid system during acute pancreatitis primarily represents an endogenous protective mechanism against pancreatic pain.
Recently, Matsuda et al21
reported prolonged survival in rats upon AM251 treatment in a model of tauro-cholate-induced necrotizing pancreatitis. Because effects of cannabinoid agonists were not reported in the study by Matsuda et al and cerulein-induced pancreatitis in mice is far less severe, non-necrotizing, and does not lead to animal death, it is difficult to directly compare the outcome of the study by Matsuda et al21
with the results described in this paper. Our results are more in line with a recent study reporting a protective role for the endogenous cannabinoid system against colonic inflammation in a mouse model of experimental colitis.9,11,22
Consistent with the above, we now show that acute pancreatitis, a visceral inflammatory disease in humans, is associated with an activation of the endocannabinoid system. Because management of visceral inflammatory diseases should ideally include antinociceptive23
as well as anti-inflammatory components, our results lay a basis for testing the therapeutic value of cannabinoids as supplements to conventional analgesic therapy.