Characterisation of the Spared Nerve Injury Model of Neuropathic Pain
Helle Kirstein Erichsen
Neuropathic pain can arise a result of peripheral or central nerve dysfunction and includes a variety of conditions that differ in aetiology as well as location. Management of neuropathic pain remains a major clinical challenge, partly due to an inadequate understanding of the mechanisms involved in the development and maintenance of neuropathic pain.
Pathophysiological changes occurring within damaged nerves as a result of injury contribute to their injury-induced activation and induce a state of prolonged neuronal hyperexcitability within the dorsal horn of the spinal cord. This state of central sensitisation is believed to contribute to the behavioural sensations of allodynia (perception of pain following normally non-noxious stimuli) and hyperalgesia (increased pain response to noxious stimuli). Numerous animal models reflecting human neuropathic pain syndromes have been developed and characterised over the last 10-15 years. These models generally involve some kind of injury to the sciatic nerve, although the method used to induce injury varies. Animals with these types of nerve injury have been shown to develop abnormal pain sensations similar to those reported by neuropathic pain patients. The spared nerve injury (SNI) model is a novel model of peripheral nerve damage that involves ligation and transection of the tibial and common peroneal nerves leaving the sural nerve intact.
The overall objective of the studies, on which this thesis is based, was to validate and characterise the SNI model of neuropathic pain, both in terms of behavioural changes, and the mechanisms underlying the development and maintenance of the pain-like behaviours, observed in these animals. To help elucidate the latter aspect, various compounds that target specific aspects of nociceptive transmission (NMDA and AMPA/kainate receptor antagonists, use-dependent Na+ channel blockers, µ-opioid receptor agonists, gabapentin and the neurotrophic factor artemin) were pharmacologically tested in the SNI model as well as in various animal models of acute, persistent, and peripheral and central neuropathic pain.
Results from the current studies have shown that the SNI procedure produces robust behavioural changes including mechanical and cold allodynia, and mechanical hyperalgesia, in a substantial number of injured animals (79%). Unlike other animal models of peripheral nerve injury, this hypersensitivity persisted for at least 15 months without any signs of remission. In addition, animals with different stages of nerve injury (3, 10 and 15 months post-SNI) were observed to respond similarly in terms of attenuation of hyperalgesia and allodynia behaviours in response to systemic administration of morphine and mexiletine, indicating that the underlying mechanisms for maintenance of pain-like behaviours are comparable in early, middle and late stages of nerve injury.
Systemic administration of the NMDA receptor antagonist MK-801 falied to attenuate the repertoire of established pain behaviors in SNI animals, suggesting that maintenance of behavioural hypersensitivity to noxious stimulation is mediated by A-fibres rather than C-fibres which are normally sensitive to NMDA receptor antagonists. Similarly, the AMPA/kainate receptor antagonist NS-1209 administered either prior to SNI-injury (24 hrs infusion) or acutely after pain behaviours were established, showed no effect on either the development or maintenance of pain-like behaviours. In contrast, NS-1209 showed marked antinociceptive properties in a range of animal models of acute and persistent pain, and in the chronic constriction injury model of neuropathic pain.
A range of use-dependent Na+ channel blockers were shown to relieve pain behaviours in animal models of persistent and neuropathic pain to a greater extent that nociceptive pain induced by acute thermal stimulation. Thus, these observations appear to reflect the ability of these use-dependent drugs only to inhibit Na+ influx during sustained depolarisation. Comparable antinociceptive properties of these use-dependent Na+ channel blockers were observed in the Gazelius and SNI models of neuropathic pain, indicating that common mechanisms may underlie the maintenance of allodynia and hyperalgesia in these rat models.
In other studies, various µ-opioid receptor agonists showed marked antinociceptive properties both in an acute thermal test and in models of peripheral and central neuropathic pain. These observations suggest that relatively minor changes in µ-opioid receptor-mediated signalling occur upon injury in these models. The current results are contrary, at least in part, with reported opioid efficacy in corresponding clinical neuropathic pain conditions of peripheral and central aetiology, where opioids have been reported to be more efficacious against peripheral rather than central neuropathic pain.
The anticonvulsant gabapentin, which is widely used in the clinical treatment of various types of neuropathic pain syndromes, was in the present study observed to alleviate mechanical allodynia, but not mechanical hyperalgesia and cold allodynia in SNI animals. Gabapentin has been reported to alleviate these pain-related behaviours in other animal models of peripheral nerve injury, reinforcing the distinct pharmacological profile of the SNI model.
Finally, in an attempt to explore the role of neurotrophic factors in the SNI model based on recently published favourable findings in a related model of neuropathic pain, the GDNF receptor agonist artemin was chronically administered to SNI animals. However, artemin had no effect on the post-injury expression of pain-related behaviours further supporting the distinct aetiological profile of the SNI model. However, technical limitations of this particular study may also have contributed to these negative findings.
In the clinical setting neuropathic pain conditions encompass a range
of heterogeneous patient populations in terms of pain symptomatology,
which are variably responsive to analgesic intervention strategies. Thus,
the use of the SNI model, which has a distinct pharmacological profile
to a range of analgesic compounds, together with other established animal
models of peripheral neuropathic pain might be expected to better contribute
to the development of novel analgesic compounds for the treatment of neuropathic