Neurotransmitters, Neuromodulators, and Ionophores in Mechanisms of Pain Persistence after Surgery: From Periphery to the Brain

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Surgery, however necessary, invariably involves incision, retraction, and compression of somatic and neuronal tissue. The subsequent persistent pain is an entirely variable and individual experience, the intensity and duration of which depends upon the balance of inflammatory and neuropathic pain to which a patient is exposed and variable mechanisms from the periphery to the brain. While this damage to non-neuronal tissue should heal, eliminating peripheral sensitized inflammatory drives to the pain state [42]; by contrast neuronal damage generates ongoing activity that is likely to persist, since healing is much less probable. This accordingly drives changes in spinal cord and brain processing of pain messages. Even small levels of peripheral activity deriving from inflammatory and/or neuropathic processes, arriving on an already sensitized CNS, may lead to abnormal pain perception, provoking allodynia and hyperalgesia. Patients that develop persistent pain are similarly more likely to develop secondary symptoms such as anxiety and depression; co-morbidities that can both decrease quality of life and participate in the enhancement of the pain state. A range of individual differences, not least genetic susceptibilities, similarly influences the persistence of pain after surgery.

Post-surgical pathophysiology can be categorized into a number of broad themes. At one level, it is simplest to partition information between the periphery, the spinal cord and the brain. But alterations in pain processing should also be viewed in terms of overall changes to the neurotransmitters, neuromodulators and ionophore systems in order to truly understand the pathophysiology behind the different sensory components of persistent pain.

AFFERENT DRIVE FROM THE PERIPHERY

The Importance of the Ionophore

As the conduction machinery of the lipid membrane, ionophores are crucial components of the transduction and transmission of sensory information. Both inflammation and nerve injury elicit plasticity in the function and expression of these ionophores, the result of which is the enhanced and spontaneous afferent drive of central excitability and maladaptive processing.

Transducers

At the site of incision ionophores are crucial, producing depolarizing currents known as generator potentials, which may elicit action potentials or simply increase the membrane potential to sensitize afferents. Some of these ionophores, such as the Acid Sensing Ion Channels (ASICs) that detect the drop in tissue pH that accompanies tissue damage, are critical to the initial nociception and sensitization following surgery [13]. There is also notable up regulation of ASIC3 expression in incision models of postoperative pain [13], which may contribute to the further sensitization of primary afferents.

Similarly TRPV1, the heat and acid sensing cation channel, has a role both in the initial detection of tissue damage but also in afferent sensitization, having been shown to mediate spontaneous firing and heat sensitization in postoperative pain [3]. These changes in afferent sensitivity and activity are brought about by both a functional up-regulation and enhancement of TRPV1 depolarizing currents by mediators such as NGF following incision [4,7]. Anti- NGF therapy in this model of postoperative pain significantly reduces guarding and heat hyperalgesia [4], revealing the significance of post translational modification and up-regulation of these ionophores.

The TRPA1 ion channel has also come under scrutiny for a role in the generation of postoperative pain. This polymodal receptor, described as the “gatekeeper for inflammation”[11], has previously been shown to have roles in both inflammatory and neuropathic mechanical hyperalgesia [7]. It is speculated that TRPA1 similarly contributes to the generation of both mechanical hypersensitivity and spontaneous pain following deep incision [53]. However, cutaneous incision models in TRPA1 KO mice contradict these findings [7]. It may be the case that TRPA1 plays a role exclusive to deep tissue procedures. In general, we have little data on how deep pains are generated and modulated. This will be a key area for future research on post-surgical pains.

As a consequence of the role, these ionophores play in generating the afferent drive, these channels and their afferent sub populations are attractive peripheral targets for pharmacological interventions, both peri- and postoperative. One approach currently entering clinical trial is the use of the high dose capsaicin patch [37], which causes the desensitization and eventual reversible degeneration of the peripheral terminals of TRPV1 primary afferents. The use of capsaicin in this manner has already proved successful in animal models of incision pain [29].

Sodium Channels

Ionophores similarly control the electrophysiological properties of the primary afferents, not least the threshold for action potential generation, interspike intervals and burst duration. Of particular importance to the transmission of pain signals, are the voltage gated sodium channels (VGSC) Nav1.3, 1.7, 1.8 and 1.9. Directly after surgery and while inflammation is ongoing, the activation of signaling cascades by inflammatory messengers lead to the phosphorylation of VGSC. Alteration in the threshold, current magnitude and kinetics of Nav1.7, 1.8 and 1.9 currents follow, increasing membrane excitability and thus the likelihood that a given stimulus will evoke an action potential [32]. This peripheral sensitization can be limited by the use of COX inhibitors, but the effects of these interventions are narrow should the postsurgical pain be largely neuropathic in nature.

In addition to these post-translational changes to ionophore proteins evoked by the inflammatory milieu, there is dynamic regulation of sodium channel expression, both in their distribution and population. Transcriptional regulation, triggered by both inflammatory cascades and nerve damage, lead to both up and down regulation of VGSC populations. Crucially, following nerve damage there appears to be a renewed expression of Nav1.3, despite restricted expression in normal adult rat DRG [14]. It is suggested that this novel expression of Nav1.3 in adult sensory afferents results in ectopic firing and consequently spontaneous pain, symptoms which can be reversed by the application of GDNF which normalizes Nav1.3 expression [14,32].

Similarly, the usually abundant Nav1.8 and 1.9 have been shown to be down-regulated following nerve injury [14,32]. However, results are contradictory given alternate studies exhibit a role for Nav1.8 in spontaneous activity in sensory afferents [43]. Gold et al argue that while Nav1.8 is down-regulated in the injured neurones, expression is redistributed to uninjured counterparts to produce aberrant activity [20], which consequently maintains an afferent drive. However, antisense for Nav1.8 fails to attenuate incision pain, suggesting the role of this sodium channel may be greater in persistent postoperative pain involving nerve injury [28].

Consideration must also be made to the enhanced action of sodium channel populations within sympathetic neurones. Nav1.7 containing sympathetic and sensory neuron populations have been shown to work in concert to enhance pain sensation [34]. While the exact mechanism of a sympathetic drive in acute and neuropathic pain is not yet clear, this system is already being targeted for analgesia in postoperative pain [33]. Future pharmacotherapy may prove more successful in preventing and treating persistent postoperative pain by blocking both sensory and sympathetic systems.

The importance of sodium channels is demonstrated in patients carrying the Single Nucleotide Polymorphism (SNP) SCN9A 3312T allele. These individuals exhibit reduced post-operative pain and likelihood of developing inadequate analgesia following pancreatectomy [16]. This SNP occurs the gene encoding Nav1.7, the VGSC which regulates release of peptide transmitters from central terminals, and consequently wind-up, as well as exerting a key role in ectopic firing in neuromas [14,34]. The pain protection provided by this SNP, which alters the gating properties of Nav1.7, demonstrates the importance of ionophores in dictating the postoperative pain experience of patients.

In controlling the excitability and output of sensory afferents, and thus the input to the spinal cord, the VGSCs present an attractive target for the prevention of activity dependent changes in central processing following surgery. By interruption of the sensory barrage, sodium channel blockers such as lidocaine provide proven short term pain relief, but their long term application may also hold the key to quenching the development of maladaptive central changes [30,57]. In the future, selective blockers of particular sodium channels could be the key to prevention of peripheral electrical drives.

Processing of Afferent Activity by the Spinal Cord

In inflammation, peripheral sensitization will produce higher levels of activity arriving in the spinal cord. The paradox between coexistent gain and loss of symptoms in neuropathic pain is associated with what appears to be compensations in the CNS for the loss of normal inputs; the sensory system adapts to loss of input due to nerve damage by opening circuits to amplify the signals from remaining intact pain fibres or to ectopic activity in afferent fibers. As a consequence, non-noxious inputs effectively synapse onto pain signaling systems.

Calcium Channels

The first synapse between the peripheral nerve and spinal neurones provides a good example of these sorts of changes. In inflammation, the calcium channel populations (N, P/Q, R and T) appear to be driven harder by the enhanced peripheral inputs. Shifts in dose-response curves of calcium channel blockers are seen [52]. After neuropathy, the loss of afferents results in an upregulation of N-type channels, with an especially marked increase in the auxillary protein, the alpha-2-delta 1. This protein, associated with trafficking of the channels, is the target for gabapentin and pregabalin [10]. Neurones in the spinal cord of animals with overexpression of this subunit exhibit abnormal patterns of firing in the absence of nerve injury, notably increased and prolonged responses to peripheral stimuli [31]. It is believed that this upregulation is the key to the ability of these drugs to modulate neuropathic pains, but not some inflammatory conditions where there is minor upregulation. Thus, in an animal model of OA, where there are additional neuropathic components, pregabalin can be effective but fails when neuropathy is lacking [50]. There are additional permissive factors that allow the gabapentinoids to work, and these are discussed later in descending controls. Issues such as these need consideration in the use of alpha-2 delta ligands in the peri-operative setting [41]. Whatever the case, the spinal neurones with projections to sensory and affective brain areas are highly likely to receive greater amounts of transmitter from the afferent fibres. This is the first stage in the induction of central sensitization.

Central Inhibitory Transmission

Pain messages can be enhanced by increases in peripheral or central excitatory mechanisms but equally, by a loss in inhibition. 30–40% of spinal neurones are inhibitory interneurones and their tonic activity is an important regulator of sensory tone in the spinal cord [49]. Prevention of local spinal cord inhibition in normal animals with GABA_A receptor antagonists or glycine receptor antagonists mimics behavioural hypersensitivities to low threshold stimuli, similar to that seen in animal models of chronic pain [58]. Thus, there is a dorsal horn pathway capable of mediating allodynia and hyperalgesia that is normally under strict inhibitory control that becomes pathologically disrupted in situations of chronic pain [51].

Central Excitatory Transmission

Alongside inhibitory controls, there are powerful excitatory systems within spinal circuits. The co-release of peptides and glutamate from incoming active peripheral nerves is likely to be enhanced in a number of pain states by the changes in calcium channel functions. These transmitters lead to activation of neurokinin and N-methyl-D-aspartate (NMDA) receptors for substance P and glutamate which in turn generate central sensitization or spinal hypersensitivity [12]. A key event in these processes is wind-up (when small fiber stimulation rapidly induces higher levels of spinal neuronal firing even though the peripheral drive remains constant), and long-term potentiation (LTP) where the frequency of stimulation to induce is very high [12,44]. In humans, the counterpart of wind-up is temporal summation [25

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