1.2 “Wiring”Problems
In patients with CP，inflammation and progressive replacement of the normal pancreatic tissue with fibrosis can lead to changes in the function and morphology of intrapancreatic nerves.Collectively these processes have been referred to as“wiring problems”（Moran et al.2015）and represents a wide spectrum of changes in peripheral nociception and central pain processing which is discussed in detail below.
1.2.1 Peripheral Changes
To understand the neurobiological perspective on pain in CP，a basic knowledge about pain perception and processing is required Depending on the excitability of the neural membrane，the stimulus sensed by a variety of nociceptors may lead to generation of an action potential，which travels along afferent nerves to the spinal end of the nerves in the dorsal horn to trigger the release of neurotransmitters，which cross the synapse and activate secondary neurons that transmit the noxious stimulus to the brain through different pathways，ultimately resulting in the sensation of pain（Anaparthy and Pasricha 2008）.
Peripheral Sensitization
Nerve growth factor，normally expressed by islets in the pancreas，is amongst the most important and well-characterized neuropeptides involved in growth，regulation and proliferation of certain neurons（Woolf et al.1994）.In rats with CP，it is upregulated.Nerve growth factor can not only significantly increase nociceptor excitability，pancreatic hyperalgesia and referred pain to somatic structures but also upregulate the nociceptor transient receptor potential vanilloid-1 in animal model of CP，as well as in humans with CP（Xu et al.2007；Toma et al.2000；Hartel et al.2006）.Thus，in preliminary studies，antagonists for transient receptor potential vanilloid-1 have been developed and proved to be effective in humans with neuropathic pain.However，hyperthermia，is still a concern of transient receptor potential vanilloid-1 antagonism（Wong and Gavva 2009）.
Release of cytokines and chemokines，such as IL-8 and fractalkine，from immune cells infiltrating the pancreas during CP has been associated with pancreatic pain（Ceyhan et al.2009a；Di Sebastiano et al.1997）.Specifically，compared to patients with painless CP，the number of mast cells can reach a 3.5 fold increase in those with pain（Hoogerwerf et al.2005；Esposito et al.2001）.A proposed mechanism is increased activation of protease-activated receptor 2，triggered by tryptase released from the mast cells（Hoogerwerf et al.2005）.Other upregulated，proinflammatory cytokines have also been suspected to play a role in the pain generation in CP，and in some cases this upregulation and resulting pancreatic neuritis may increase pain intensity and/or frequency（Bockman et al.1988；Keith et al.1985；Ceyhan et al.2009b）（for a thorough review see（Fasanella et al.2007））.
Additionally，upregulation of neurotransmitters involved in pain signalling at the central end of the nociceptor，such as calcitonin gene-related peptide，substance P and brain-derived neurotrophic factor，has been demonstrated in animals with CP along with increased sensory nerve excitability，and pharmacological blockade of these receptors has likewise been shown to reduce pain（Hughes et al.2011；Liu et al.2011；Büchler et al.1992）.
These functional alterations render the nociceptors more sensitive to further stimulation（Gebhart 2000；Anand et al.2007）.This so called peripheral sensitization，results in an increased barrage of pain signals to the spinal cord（Woolf and Salter 2000），which is believed to increase clinical pain intensity，can be an important factor in the pathogenesis of pain in CP（Bockman et al.1988；Keith et al.1985；Ceyhan et al.2009c）.
PeripheralNeuropathy
Besides the changes on the molecular level，CP is also associated with prominent morphological and/or functional alterations of pancreatic nerves（Bockman et al.1988；Ceyhan et al.2009c）.These changes are collectively referred to as“neural plasticity”at the cellular（neuronal）level.The characteristic features of pancreatic nerves in human CP are increased neural density（neural sprouting），increased neural size（neural hypertrophy），and perineural inflammations（neuritis）（Ceyhan et al.2009c；Friess et al.2002；Demir et al.2015）.In addition to the morphological alterations it has been demonstrated that nerves in patients with CP contain fewer sympathetic or adrenergic nerve fibres than normal pancreatic tissue—a phenomenon referred to as neural remodelling（Ceyhan et al.2009b）.Although these changes in many cases have been shown to relate to sensation in CP，the mechanisms and interactions with the functional neural changes are not fully understood（Demir et al.2015）（Table 5.1）.
Table 5.1 Peripheral pain mechanisms in chronic pancreatitis and its associated experimental evidence
1.2.2 Central Changes
Central Sensitization
An augmented signalling of noxious stimuli to the spinal cord induces increased responsiveness of central pain transmitting neurons and thereby increases the gain in the whole pain system.This phenomenon is known as central sensitization leading to intense peripheral noxious stimuli，tissue injury，or nerve damage（Woolf 2011；Latremoliere and Woolf 2009）.The process it typically characterised by increased excitability，expansion of the dorsal horn neurons receptive field and by sprouting of non-nociceptive afferents into“pain-specific”areas of the spinal cord.These functional and structural changes explain the clinical and experimental findings associated with central sensitization:
·primary hyperalgesia:increased sensitiveness to painful stimuli of the diseased organ（e.g.increased sensitiveness to stimulation of the pancreas）
·secondary hyperalgesia:a receptive field expansion that enables input from non-injured tissue to produce pain（e.g.increased sensitiveness to stimulation of visceral organs remote to the pancreas such as the rectosigmoid orsomatic structures）
·allodynia:pain in response to a non-noxious stimulus（e.g.postprandial pain reported by patients with CP）
Several experimental human pain studies have reported increased areas of referred pain and augmented pain sensitiveness was seen in CP patients corresponding to primary and secondary hyperalgesia as discussed above（Dimcevski et al.2007）.Along this line，additional studies reported decreased pain thresholds to somatic stimulation of muscle and bone as well as stimulation of the rectosigmoid（Olesen et al.2010a；Buscher et al.2006）.The latter reflects a special form of secondary hyperalgesia（viscero-visceral hyperalgesia）seen in visceral pain disorders accompanied by central sensitization.(https://www.daowen.com)
Many patients with CP report postprandial pain，which，in addition to changes in ductal or parenchymal pressure mediated by humeral mechanisms，may also reflect allodynia triggered by non-noxious mechanical stimuli when the food passes the upper segments of the gastrointestinal tract in close proximity to the pancreas.In a sensitized pain-system，food passage may activate previous non-nociceptive neurons that now covey noxious information due to e.g.，sprouting into pain signalling areas of the spinal cord.This again leads to allodynia perceived as postprandial pain by the patient.
One of the best characterised mechanisms involved in central sensitization is activation of the N-methyl-D-aspartic acid（NMDA）receptor，thus revealing a key involvement of glutamate in this process（Willert et al.2004）.Blocking of the NMDA receptor by ketamine has been shown to reverse hyperalgesia associated with CP in an experimental study（Bouwense et al.2011a）and ketamine is currently under investigation in a randomised placebo controlled-trial of painful CP（Juel et al.2015）.Also，changes in ion channel properties have been shown to play a key role in the process of central sensitization.These can be modulated by gabapentoids，such as gabapentin and pregabalin，which target the pre-synaptic voltage-dependent calcium channels.In patients with CP，pregabalin is effective as an adjuvant treatment of pain in patients with CP and reverse associated primary and secondary hyperalgesia.Interestingly its effect can be predicted by segmental hyperalgesia of the pancreatic viscerotome（the upper abdominal skin area sharing spinal innervation with the pancreatic gland）and，as such，pregabalin treatment can be tailored to the individual patients pain profile（Olesen et al.2013a）.
Taken together，these clinical，experimental，and pharmacological findings characterise a generalised hyperalgesic state of the pain system in patients with CP and likely mirrors widespread sensitization of central pain pathways.The abnormalities seem to be linked to disease severity and at some point may become independent of the peripheral nociceptive input（see discussion later）（Bouwense et al.2013）.
Abnormal Patterns of Cortical Activity
Several studies have indicated that deafferentation，chronic pain，and hyperalgesia，as seen in CP patients，are associated with a functional reorganisation of the brain areas involved in sensory processing（Flor et al.2006）.Accordingly，people with arm or hand amputations show a shift of the mouth into the hand representation in the primary somatosensory cortex，with the quantity of cortical reorganisation being correlated with subjective pain ratings（Flor et al.1995）.In patients with CP，pancreatic nerve damage and modulation may to some degree mimic the peripheral nerve pathology seen in patients following amputations.Along this line，experimental pain studies have indicated that chronic pain and hyperalgesia is associated with functional reorganisation of the visceral sensory cortex（Dimcevski et al.2007；Olesen et al.2010b；Lelic et al.2014）.Hence，CP patients show reorganisation of the brain areas involved in visceral sensory processing.In addition，the evidence of impaired habituation to noxious stimuli in CP patients possibly reflecting a cortical neuronal hyperexcitability（Olesen et al.2013b）.Functional reorganization and hyperexcitability may be reversed by transcranial magnetic stimulation and a shamcontrolled randomised trial has documented the effectiveness of this technique for pain alleviation in patients with CP.
The thalamus，as a critical relay site in the sensory system，has been implicated in chronic pain.Hence，a disturbance of the thalamocortical interplay evidenced by global changes in the rhythmicity of the cerebral cortex was observed in patients with neuropathic pain of mixed origin（Sarnthein et al.2006）.Parallel findings were observed in CP patients in studies based on spectral analysis of visceral evoked brain potentials and resting state electroencephalography（Olesen et al.2011；Drewes 2008）.Remarkably，changes in brain oscillations following pregabalin treatment have been associated with its analgesic efficacy（Graversen et al.2012）.Thus，in addition to a spinal effect on central sensitization，the analgesic effect of pregabalin may also be mediated by supraspinal mechanisms.
Structural Cortical Alterations
With advanced imaging technology，the correlation of structural cortical alterations and hyperexicitability was found.In one study，diffusion weighted MRI demonstrate the link between microstructural changes in the insular and frontal brain areas and clinical pain intensity and functional scores（Frøkjær et al.2011）.Pain intensity was proportional to the severity of microstructural abnormalities（Mullady et al.2011）.In another MRI based cortical volumetry study，a reduced brain areas involved in visceral pain processing suggested a central neurodegenerative response to severe and chronic pain（Frøkjær et al.2012）.Whether such structural changes represent specific signatures of pancreatic pain has yet to be determined，but evidence from other chronic pain diseases suggest that morphological changes of brain structure may be unique for different pain conditions and，as such，it suggests the possibility of unique therapies by targeting the underlying specific pathways for each type of chronic pain（Apkarian et al.2011）.
Changes in Spinal Interneurons and Pain Modulation
The pain system has several inherent mechanisms whereby inflowing pain signals are modulated.Among many mechanisms，inhibitory spinal interneurons and descending modulatory pathways from the brain stem and higher cortical structures plays a key role.Such endogenous pain modulation control the afferent input of nociceptive signals at the spinal level and the process can lead to either facilitate or inhibit the spinal transmission of pain to brain（Heinricher et al.2009）.Facilitation have been implicated in the form of chronic pain and several studies have documented the involvement of brainstem structures in the generation and maintenance of central sensitization and hyperalgesia（Zambreanu et al.2005；Gebhart 2004）.Impaired inhibitory modulation was reported in painful CP patients base on human model（Olesen et al.2010a；Bouwense et al.2013）.In addition，brainstem facilitation was reported to maintain pancreatic pain in an animal model of CP（Vera-Portocarrero et al.2006）.Until today，no studies have attempted to modulate pain modulation in patients with CP，but emerging evidence from other chronic pain conditions suggest that selective serotoninnoradrenaline reuptake inhibitors（SNRIs）may be useful to augment descending inhibitory modulation and thereby to relieve pain（Yarnitsky et al.2012）.In Fig.5.1 a schematic illustration of the different mechanisms is shown.
Fig.5.1 Schematic illustration of the different nervous mechanisms thought to be involved in pancreatic pain.（1）Peripheral nerve damage with ectopic activity resulting in stimulus dependent and spontaneous pain；（2）Sprouting of non-nociceptive nerve afferents into“pain specific”areas of the spinal cord resulting in allodynia；（3）Sprouting of sympathetic neurons（black）into the dorsal horn neurons rendering the system sensitive to sympathetic activity and catecholamine；（4）Sensitization and phenotypic changes of spinal neurons due to the increased afferent barrage；（5）Defects in the normal inhibition from（a）interneurons and（b）descending tracts arising in the brainstem（black）；（6）Abnormal coding of the afferent input from somatic areas and other viscera resulting in increased referred pain and viscero-visceral hyperalgesia；（7）Reorganisation and structural changes in the brain that encodes complex sensations such as affective，evaluative and cognitive responses to pain
Are Changes in Central Pain Processing Depending on a Nociceptive Input from the Pancreatic Nerves？
As can be seen from the above sections，several lines of evidence indicate that central pain processing is abnormal in CP.However，from the current evidence it is difficult to determine whether these central abnormalities depend on a nociceptive input from the pancreatic nerves（Gebhart 2007）.There is support from other diseases such as in peripheral nerve injury and painful polyneuropathy that regardless of signs of central sensitization，primary afferent input is critical for maintaining on going and evoked neuropathic pain（Haroutounian et al.2014；Vaso et al.2014）.The efficacy of topically applied drugs in these conditions also supports peripheral pain-generating mechanisms（Backonja et al.2008；Meier et al.2003）.A small cross-sectional study in CP patients found that in hyperalgesic patients the generation of pain was independent of the pancreatic nociceptive drive and consequently denervation of pancreatic nerves was ineffective（Bouwense et al.201 lb）.However，larger and longer-term studies that include systematic evaluation of the pain system prior and after intervention are still needed for confirmation（Table 5.2）.
Table 5.2 Central pain mechanisms in chronic pancreatitis and associated experimental and clinical manifestations