The enigma of visceral pain

Visceral pain as a topic remains slightly enigmatic. We deal with these cases everyday. Like much of our pain practice, the theoretical understanding outweighs the options we have available to treat. Let’s take a look at the underlying neuroanatomy and consider what options we do have.



Where does the pain originate from?

Visceral pain may result from;

-Inflammation of a visceral organ - pancreatitis

-Obstruction to bile or urine flow – biliary or ureteral obstruction

-Functional visceral disorders ie: IBD

-Distension of viscera

-Interstitial cystitis

-Gastro-oseophagela reflux

-Cancer pain = 28% of cancer pain in people is attributed to be visceral in origin


Visceral pain is often accompanied by other symptoms such as nausea, vomiting and sweating. Perhaps due to a lack of self-reporting in our veterinary species we are limited in how we recognise these clinical signs and their link to VP.


Neuroanatomy

Visceral nociceptors are different from non-visceral nociceptors. Afferent nerves are associated with autonomic nerves but are not part of these autonomic pathways. These afferents terminate in the dorsal root ganglion (DRG) or travel via the vagus nerve and terminate in the brainstem. 80% of visceral DRG somata have C fibres whereas fewer than 40% have A-delta fibres. Visceral A-beta fibres are rare.


Spinal visceral afferents terminate in lamina V of the dorsal horn, around the central canal and in lamina X. Cutaneous nociceptive afferents terminate throughout the dorsal horn. Non visceral nociceptive afferents also terminate in the same layers as visceral and so converge on the same second order neurons - this means that co-input from either somatic or visceral pain has potential to increase nociceptive traffic in second order neurones.


Most organs have an intrinsic innervation ie: the enteric nervous system of the gut. Most organs are innervated by two different extrinsic nerves – the urinary bladder is innervated by the pelvic and splanchnic nerves.


Visceral nociceptors only have two types of specialised ending compared to non-visceral which have several (ie: Pacinian corpuscle). The two types are intraganglionic laminar endings (IGLEs) and intramuscular arrays (IMAs). They have limited distribution. They are low threshold mechanoreceptors and less effective at detecting noxious events, compared to their non-visceral counterparts. Many spinal visceral afferents will have primitive endings. Visceral nociceptors can detect chemical stimuli.


Despite this, visceral afferents encode signals from low threshold stretch that also encode into the noxious range.


Fibre types differ between visceral afferents

Visceral afferent populations differ and are considered a non-homogenous population. The bladder and colon are innervated by afferents within the splanchnic and pelvic nerves with cell bodies in the thoracolumbar and lumbosacral DRG respectively. Mesenteric afferents make up half the splanchnic afferent but are not found in the pelvic nerve. Muscular and mucosal afferents are reported in the pelvic nerve but not in the splanchnic nerve.


Chemical differences are apparent between these subpopulations with more splanchnic nerves responding to bradykinin that pelvic afferents. Serosal afferents are equally represented in splanchnic and pelvic nerves - these have a differential sensitivity of TRPV1 receptors. The colon is innervated by five different fibre types – mucosal, muscular mucosal, muscular, serosal and mesenteric. Therefore it can be said that the signal transmitted by one organ as VP is not the same as a signal transmitted from a different organ.


The character of visceral pain explained

Visceral pain is diffuse in character and difficult to localise. Viscera are sparsely innervated compared to skin. Less than 7% spinal afferents project to viscera compared to >50% in skin. Visceral terminations in the spinal cord arborise widely across several segments and even to the contralateral spinal cord. Spinal neurons that receive visceral input also receive convergent input from skin or other structures (including other viscera), which is how referred pain is produced and why VP can be difficult to localise.


Experimental colitis increases bladder sensitivity. Cross organ sensitisation is a result of convergence in the same spinal segment. Similarly, IBS individuals have a greater incidence of urinary bladder sensitivity. Another mechanism is dichotomised sensory fibres whereby one afferent innervates two organs.


In humans there is an association between IBD and musculoskeletal pain, linked by central sensitisation. Could this be relevant for dogs with IBD and osteoarthritis? Does the control of IBD influence the pain of OA? This could represent a challenge in these patients that may not tolerate the first line OA options of NSAIDs or grapiprant. In these cases bedinvetmab represents an sensible option as a first line option for OA, plus there could be a role for nerve growth factor in VP.


Ion channels and neurotransmitters

Calcitonin gene related peptide (CGRP)

70-90% of visceral cell bodies stain positive with antibody for CGRP compared to a lot less for non-visceral. Afferent neurons that bear the CGRP marker are labelled peptidergic. These express the nerve growth factor receptor, tropomyosin kinase (TrKA). 75% of bladder somata and 43% of skin somata express TrKA.

Currently we do not have an antagonist for CGRP, however by targeting nerve growth factor (NGF) in theory this will reduce CGRP centrally. There are monoclonal antibodies against CGRP in people and it is therefore possible that a pharmaceutical company will look to develop these in dogs or cats. NGF mRNA is increased in IBD and anti-NGF agents are effective in preclinical distension models – so there could be a role for these drugs in treating VP.


TRPV1

TRPV1 is sodium channel which is sensitive to heat – known as the capsaicin receptor.

The majority of visceral DRG somata test positive for TRPV1, suggesting that this is a significant pathway for transmission of VP. Animals lacking TRPV1 receptors in the colon are significantly less sensitive to colonic distension. TRPV1 also play a role in bladder sensitivity, especially in interstitial cystitis and a significant role in GI inflammation.

TRPV1 co-localise with the TrKA receptor. TRPV1 is selectively expressed on peptidergic neurons which are neurons that express CGRP and substance P (sP). This release produces neurogenic inflammation. TRPV1 is upregulated in IBD and stays upregulated once the IBD is treated. TRPV1 is also upregulated in pancreatitis.


TRPA1 is upregulated in colitis.

TRPV4 may play a role in the colon.


Acid Sensing Ion Channels

Activated below pH 7.4.

Inhibited by diclofenac.

Mediator of cardiac pain.


Voltage-gated calcium channels

When gabapentin binds to the alpha delta subunit this means sP and CGRP cannot be released from the primary afferent. This only occurs when channels are upregulated and activated in a pathological state. Gabapentin has been shown to reduce visceral hypersensitivity in experimental animals.


Peripheral kappa opioid receptors

Are found on visceral afferents and thought to act as a modulator of visceral pain. Butorphanol infusions are suggested as an option for managing the pain of pancreatitis.


NMDA

Opening of the receptor is associated with visceral hyperalgesia with NMDA receptors found on afferents from colon and bladder.

Memantine IV in rodents has been shown to block the response to colorectal distension, suggesting potential rationale for memantine or amantadine in VP.


Further work is required regarding paracetamol in VP. Pre-clinical studies show a synergy between NSAIDs and paracetamol however the use of NSAIDs may not be beneficial in all circumstances.


An understanding of the types of receptors and neurotransmitters involved in the transduction and transmission of VP give some insight into which analgesics potentially play a role. Visceral pain has acute, chronic and acute on chronic presentations which are all equally challenging to treat.


References

Davis MP. Drug management of visceral pain: concepts from basic research. Pain Res Treat. 2012;2012:265605. doi:10.1155/2012/265605


López-Pérez AE, Nurgali K, Abalo R. Painful neurotrophins and their role in visceral pain. Behav Pharmacol. 2018 Apr;29(2 and 3-Spec Issue):120-139. doi: 10.1097/FBP.0000000000000386. PMID: 29543647.


This post was written by Matt Gurney.


Matt sees referrals in the pain clinic at Anderson Moores Veterinary Specialists. You can also receive telemedicine advice from us here if you have a pain case where you need a helping hand.


Matt & Carl established Zero Pain Philosophy to provide educational resources & telemedicine to veterinary professionals enabling optimal management of pain.


Matt Gurney is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and works at Anderson Moores Veterinary Specialists. Matt is President of the European College of Veterinary Anaesthesia & Analgesia.


Carl Bradbrook is an RCVS & European Specialist in Veterinary Anaesthesia & Analgesia and is President of the Association of Veterinary Anaesthetists. Carl works at Anderson Moores Veterinary Specialists.


The intended audience for this pain update is veterinary professionals. This pain update is based on clinical experience and independent opinion.

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