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g anglia in rats. In their experiment, they surgically dener­vated posterior branches of bilateral T5 –L2 DRG, SP expression remained >60% in the pancreas. Moreover, after high doses of capsaicin were injected to destroy pri­mary sensory afferents, the remainder of SP protein levels was still >50% in the pancreas. This suggested that half of SP origin were from intrapancreatic ganglia [20]. In the case of pancreatitis, intrinsic SP secretion could be a clue to an autoamplification loop that contributes to acinar cell death. SP executes its function by binding to neurokinin receptors (NK1). Among several inflammatory disease models, the association of SP/NK1R signaling and its con­tribution to AP through neurogenic inflammation has been well demonstrated. In a recent study, Tskuamato etal. also demonstrated anti- inflammatory action of the NK1R antagonist in a mouse model of AP. Their study results showed NK1R antagonist completely inhibited blood IL- 6levels and subsequently NK kappa B pathway in mast cells[21]. Reduction in IL- 6 and a blockade of a potent inflammatory pathway could be promising in decreasing edema, microcirculatory dysfunction, and ultimately pancreatic tissue injury in patients with acute pancreatitis. Han etal. also confirmed a well- established idea that pancreatic SP- NK1R signaling pathways were markedly upregulated in patients with acute pancreatitis. In their experiment, the use of an herbal medicine (con­taining baicalin, emodin, maglol- immunomodulators, and analgesics) that is commonly used for the manage­ment of acute pancreatitis was shown to reduce both pain and the severity of AP via blocking neuron activation­mediated pancreatic SP- NK1R signaling pathways [22]. Reduced activation of SP- NK1R signaling reduces the downstream inflammatory pathway, which subsequently reduces acinar cell necrosis. Their study also emphasized the idea that inflammation and pain positively reinforce each other, therefore, minimizing pain is considered a potential strategy to mitigate inflammation [23]. Interestingly, Green etal. recently challenged our current understanding of the NK-

The majority of pancreatic afferents express receptors on their pancreatic terminals that can induce activation and calcium influx into the presynaptic terminal, which can contribute to the release of inflammatory molecules (Fig. 15.2). The receptors in sensory endings that have received the most attention in recent years are the tran­sient receptor potential cation channel subfamily vanil­loid type 1 and 4 (TRPV1, TRPV4), a related family member TRP ankyrin 1 (TRPA1) and protease- activated receptor 2 (PAR2). They can be stimulated by numerous endogenous molecules including anandamide (an endog­enous cannabinoid), protons, leukotriene B4, hydrogen peroxide, and products of lipid peroxidation such as

Numerous studies have demonstrated that TRPV1 is involved in peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli[32]. The role of TRPV1 phosphorylation by protein kinase A/C in the development of inflammatory hyperalgesia is well established [33]. During inflammation, protein kinases phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. Interestingly, a calcineurin inhibitor, Tacrolimus (an immu­nosuppressant drug) enhances TRPV1 function by reducing

Moreover, the cooperative interaction between PAR2 and TRPV1, TRPV4 and TRPA1has been established in hyperalgesia, inflammation, and edema[41]. In the pan­creas, trypsin released from the injured pancreatic aci­nar cells directly activates PAR2, which subsequently sensitizes TRPV1. Their interaction causes neurogenic inflammation in pancreatic tissue[42]. PAR2 can also be activated via tryptase, a substance released from an acti­vated mast cell. When mast cells degranulate and release tryptase, this produces nociception by binding to PAR2 on primary afferents[43–45]. In an experimental animal model Kido et al. illustrated that an agonist of PAR2induced nociceptive pain behavior and a selective

stimulation of pancreas exocrine function[62]. Since the vagus nerve contains both parasympathetic and sensory fibers, the specific anti- inflammatory mechanism remains unclear; however, these studies have demon­strated that manipulation of the vagus nerve (e.g., vagal inhibitor) could be a potential treatment for pancreatitis.

Although nerve- targeted interventions effectively reduce pancreatitis symptoms in preclinical models, in most experimental paradigms these interventions are applied either simultaneously with the disease- inciting stimulus (e.g., caerulein) or early in the disease process. Thus, their relevance for treatment of patients is unclear, especially for acute pancreatitis where the primary symptom of pain is treated medically with nonsteroidal anti- inflammatory drugs and opioids. Clinicians are reluctant to use more aggressive procedures that include injections into splanch­nic nerves or celiac ganglia due to occasional adverse effects that can be severe and difficult to justify for a dis­ease that in many cases resolves relatively quickly. However, for chronic pancreatitis, nerve injections are an important option. There are three primary techniques that are uti­lized to manage intractable pancreatic pain: celiac plexus block (CPB), celiac plexus neurolysis (CPN), and thoraco­scopic splanchnic denervation (TSD). Importantly, there is little or no evidence that these treatments affect non-

analysis of 16 studies reveals that TSD significantly reduces pain and improves quality of life. However, the pain returns in half of those initially achieving relief after just 1.5 years [68,69]. There are many possible explanations for why TSD may not provide complete and lasting pain relief. During the surgical procedure, damage to nearby intercos­tal nerves or incomplete denervation of the thoracic splanchnic nerves (greater, lesser, least) may contribute to residual pain. However, the splanchnic nerves carry not only sensory fibers, but sympathetic fibers as well. Given that sympathetic activity suppresses pancreas function, the loss of this brake following denervation could result in hypersecretion of digestive enzymes that exacerbates inflammation and pain. Furthermore, some patients may have progressed to sensitization of the CNS meaning that they will continue to experience pain and hypersensitivity in the absence of peripheral input. Separately, the pancreas is still innervated by the vagus. While the role of vagal sen­sory afferents in pancreatic nociception has not been thor­oughly investigated, it is possible that these fibers, which remain intact, are also contributing to the recurrence of chronic pain. Further studies will be needed to parse out the underlying cause for some patients to develop persis­tent pain following TSD.

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