Perception of gastro-oesophageal acid reflux

Perception of gastro-oesophageal reflux

Peripheral mechanisms

Gastrointestinal pain is mediated by spinal visceral afferent fibres, with a probable importantcontribution from vagal afferent fibres [6]. When activated,mechanoreceptors and chemo-sensitive receptors (resident in mesentery, serosa and submucosa) epolarise Ad- and C-fibres. The ability to transduce noxious mechanical, chemical or thermal stimuli into generator currents able to depolarize such fibres is a property of transducer channels such as transient receptor potential (TRP) channels. TRPV1, TRPV4 and TRPA1 channels have been shown to have a role in GI nociception, as have acid sensing ion channels (ASICs) and P2x purinoceptors.( Knowles CH , et al ,2009)

In the presence of tissue inflammation or injury there is an up-regulation of pain transmission. The ability to enhance pain transmission to the brain in these situations is important as heightened bodily awareness can alter behaviour to aid in the protection of injured sites and the promotion of healing. Research in somatic pain has suggested that both peripheral and central mechanisms can increase nociceptive transmission following inflammation or injury to tissues. Peripheral mechanisms include peripheral sensitisation (PS), which is an inflammatory mediator-induced facilitation of nociceptor activity in peripheral tissues. Peripheral sensitisation causes pain hypersensitivity at the site of injury or inflammation, also known as primary hyperalgesia. Here inflammatory products including bradykinin, histamine, 5HT, prostanoids, proteases and cytokines permit nociceptor firing at reduced thresholds.( Hobson AR, et al , 2008)

Central mechanisms

Spinal mechanisms In normal circumstances, the presence of stimuli will activate the peripheral receptors as mentioned above. Action potentials would then be generated via activation of Na/K channels and impulses will be sent to the spinal cord via peripheral afferent nerves. Repetitive stimulation or high intensity stimuli can cause a constant firing of action potential to the spinal cord. Enhanced nociceptor input in turn activates intracellular signalling cascades within spinal dorsal horn neurones,

leading to central sensitisation and amplified responses to noxious and innocuous inputs due to facilitated excitatory synaptic responses and depressed inhibition This facilitation is triggered by the pre-synaptic release of neurotransmitters and neuromodulators such as glutamate .( Woolf CJ,,2000)

brain derived neurotrophic factor (BDNF) and prostaglandins . These neurotransmitters and neuromodulators activate ligand-gated ion channels (NMDA-receptor-glutamate), metabotrophic receptors (metabotrophic glutamate receptor (mGluR)–glutamate and NK1–substance P) and tyrosine kinase receptors (Tyrosine Kinase (Trk) B–BDNF) and increase intracellular calcium via release from intracellular stores and calcium inflow. Consequently, calcium-dependent enzymes such as protein kinase A [31], protein kinase C  and tyrosine kinases are activated, leading to phosphorylation of the NMDA receptors. (Siddiqui A, et al , 2005)This dramatically changes NMDA-receptor kinetics and reduces its voltage-dependent magnesium block, thus augmenting its subsequent responsiveness to glutamate and increasing synaptic strength, enabling previously subthreshold inputs to activate the cell. This increase in gain alters receptive field properties and pain sensitivity, causing tissue hypersensitivity far beyond the site of injury. In addition to producing central sensitisation, which occurs within seconds of appropriate activation of spinal dorsal horn neurones, nociceptive input also generates an activity-dependent change in transcription in dorsal root ganglion and dorsal horn neurones These changes occur in response to a complex mechanism involving both an increase and a modification of constitutively .( Woolf CJ,et al ,1991)


Cortical mechanisms

A major limitation of most visceral hypersensitivity studies is that they rely on subjective methods of reporting sensation intensity .To overcome this, a commonly used neurophysiological technique, cortical evoked potentials (CEP), has been adopted for use as a more objective correlate of oesophageal sensation. CEP allow recording of cortical neuronal electrical fields generated in response to a peripheral nerve stimulus. Signal averaging of cortical electrical activity of up to 200 oesophageal stimuli is conducted to generate an optimal signal to noise ratio and a temporal pattern of cortical activation is obtained. Because of the excellent temporal resolution of this technique (one ms) it is possible to study the conduction velocity of afferent neuronal transmission from the oesophagus to the cortex. Using this technique before and after oesophageal acid infusion a consistent reduction in CEP latency to oesophageal electrical stimulation has been described which demonstrates that facilitation of afferent pathway conduction accompanied the CS.( Sarkar S et al,2001)

In a recent study in NERD and functional heartburn patients there was a correlation between pain threshold and acid exposure,with increased oesophageal sensitivity being associated with lower DeMeester score . Thus reflux negative (functional heartburn) patients had lower pain thresholds when compared to both reflux positive patients and controls. Cortical evoked potentials were normal in reflux negative patients butsignificantly delayed in the reflux positive group. This suggests that increased oesophageal pain sensitivity in functional heartburn patients is associated with heightened afferent sensitivity as normal latency evoked potential responses could be elicited with reduced afferent input. Similar differentiation in the afferent response using cortical evoked potentials has also been shown in subgroups of patients with Non Cardiac Chest Pain .( Hobson AR, et al ,2006)

Functional Magnetic Resonance imaging has also been used to study the brain processing of acid induced oesophageal hypersensitivity. Lawal A et al studied the brain processing to mechanical stimulation of the proximal oesophagus following infusion of acid or control buffer solution into the distal oesophagus. Following distal oesophageal acid infusion, both subliminal and liminal levels of proximal oesophageal distentions, caused a significant increase in brain activity in both the  ingulate and the insular cortices in comparison to the control buffer solution . This suggests the development of acid-induced sensitisation of the oesophagus to mechanical distention and indicates that this sensitisation is accompanied by increased activity in brain areas processing both sensory (insular cortex) and cognitive (cingulated cortex) aspects of sensation. (Lawal A,et al ,2008)