Richard J. Mannion

Neuropathic pain: aetiology, symptoms, mechanisms, and management

We highlight current theories about peripheral neuropathic pain and show that progress in management is contingent on targeting treatment not at the aetiological factors or the symptoms but at the mechanisms that operate to produce the symptoms. This approach will require substantial progress in our understanding of the pathophysiology of neuropathic pain, the development of accurate diagnostic tools to discover what mechanisms contribute to the pain syndrome in an individual, and effective treatments aimed specifically at the mechanisms.

Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons

We have cloned a second tetrodotoxin-resistant (TTX-R) sodium channel α subunit, SNS2, with the same amino-acid sequence as a putative sodium channel α subunit NaN (ref. 1). SNS2 expression in HEK293T cells produced a TTX-R voltage-gated sodium current with faster kinetics and a lower TTX IC50 than the previously cloned sensory-neuron-specific sodium channel, SNS/PN3 (Refs 2, 3). SNS2 was co-expressed with SNS/PN3 in small DRG neurons.

Diversity of Expression of the Sensory Neuron-Specific TTX-Resistant Voltage-Gated Sodium Ion Channels SNS and SNS2

The differential distribution of two tetrodotoxin resistant (TTXr) voltage-gated sodium channels SNS (PN3) and SNS2 (NaN) in rat primary sensory neurons has been investigated. Both channels are sensory neuron specific with SNS2 restricted entirely to those small dorsal root ganglion (DRG) cells with unmyelinated axons (C-fibers). SNS, in contrast, is expressed both in small C-fiber DRG cells and in 10% of cells with myelinated axons (A-fibers). All SNS expressing A-fiber cells are Trk-A positive and many express the vanilloid-like receptor VRL1. About half of C-fiber DRG neurons express either SNS or SNS2, and in most, the channels are colocalized. SNS and SNS2 are found both in NGF-responsive and GDNF-responsive C-fibers and many of these cells also express the capsaicin receptor VR1. A very small proportion of small DRG cells express either only SNS or only SNS2. At least four different classes of A- and C-fiber DRG neurons exist, therefore, with respect to expression of these sodium channels.

Hsp27 Upregulation and Phosphorylation Is Required for Injured Sensory and Motor Neuron Survival

Peripheral nerve transection results in the rapid death by apoptosis of neonatal but not adult sensory and motor neurons. We show that this is due to induction and phosphorylation in all adult axotomized neurons of the small heat shock protein Hsp27 and the failure of such induction in most neonatal neurons. In vivo delivery of human Hsp27 but not a nonphosphorylatable mutant prevents neonatal rat motor neurons from nerve injury-induced death, while knockdown in vitro and in vivo of Hsp27 in adult injured sensory neurons results in apoptosis. Hsp27s neuroprotective action is downstream of cytochrome c release from mitochondria and upstream of caspase-3 activation. Transcriptional and posttranslational regulation of Hsp27 is necessary for sensory and motor neuron survival following peripheral nerve injury.

A Novel Tool for the Assessment of Pain: Validation in Low Back Pain

Joachim Scholz and colleagues develop and validate an assessment tool that distinguishes between radicular and axial low back pain.

Pain mechanisms and management: a central perspective.

Abstract: Although pain is always intense and unpleasant, the capacity to experience this sensation is, under normal circumstances, fundamental to the preservation of bodily integrity. Clinically, however, after injury to peripheral tissue or directly to the nervous system, spontaneous and evoked pain manifest that serve no physiologic function, are crippling to patients, and are difficult to treat. Here, we review the specific role of the dorsal horn of the spinal cord in the mechanisms of nociceptive protective pain and the spinal plasticity that occurs after nerve and tissue injury. This spinal neuronal plasticity is shown to be a key contributor to pathologic pain hypersensitivity. The potential for the molecular mechanisms responsible for the spinal plasticity in revealing new targets for future treatment is also discussed.

Collateral Sprouting of Uninjured Primary Afferent A-Fibers into the Superficial Dorsal Horn of the Adult Rat Spinal Cord after Topical Capsaicin Treatment to the Sciatic Nerve

That terminals of uninjured primary sensory neurons terminating in the dorsal horn of the spinal cord can collaterally sprout was first suggested by Liu and Chambers (1958), but this has since been disputed. Recently, horseradish peroxidase conjugated to the B subunit of cholera toxin (B-HRP) and intracellular HRP injections have shown that sciatic nerve section or crush produces a long-lasting rearrangement in the organization of primary afferent central terminals, with A-fibers sprouting into lamina II, a region that normally receives only C-fiber input (Woolf et al., 1992). The mechanism of this A-fiber sprouting has been thought to involve injury-induced C-fiber transganglionic degeneration combined with myelinated A-fibers being conditioned into a regenerative growth state. In this study, we ask whether C-fiber degeneration and A-fiber conditioning are both necessary for the sprouting of A-fibers into lamina II. Local application of the C-fiber-specific neurotoxin capsaicin to the sciatic nerve has previously been shown to result in C-fiber damage and degenerative atrophy in lamina II. We have used B-HRP to transganglionically label A-fiber central terminals and have shown that 2 weeks after topical capsaicin treatment to the sciatic nerve, the pattern of B-HRP staining in the dorsal horn is indistinguishable from that seen after axotomy, with lamina II displaying novel staining in the identical region containing capsaicin-treated C-fiber central terminals. These results suggest that after C-fiber injury, uninjuredA-fiber central terminals can collaterally sprout into lamina II of the dorsal horn. This phenomenon may help to explain the pain associated with C-fiber neuropathy.

Intact sciatic myelinated primary afferent terminals collaterally sprout in the adult rat dorsal horn following section of a neighbouring peripheral nerve

Peripheral nerve section induces sprouting of the central terminals of axotomized myelinated primary afferents outside their normal dorsoventral termination zones in lamina I, III, and IV of the dorsal horn into lamina II, an area that normally only receives unmyelinated C‐fiber input. This axotomy‐induced regenerative sprouting is confined to the somatotopic boundaries of the injured nerve in the spinal cord. We examined whether intact myelinated sciatic afferents are able to sprout novel terminals into neighbouring areas of the dorsal horn in the adult rat following axotomy of two test nerves, either the posterior cutaneous nerve of the thigh or the saphenous nerve. These peripheral nerves have somatotopically organized terminal areas in the dorsal horn that overlap in some areas and are contiguous in others, with that of the sciatic central terminal field. Two weeks after cutting either the posterior cutaneous or the saphenous nerve, intact sciatic myelinated fibers labelled with the B fragment of cholera toxin conjugated to horseradish peroxidase (B‐HRP) sprouted into an area of lamina II normally only innervated by the adjacent injured test nerve. This collateral sprouting was strictly limited, however, to those particular areas of the dorsal horn where the A‐fiber terminal field of the control sciatic and the C‐fiber terminal field of the injured test nerve overlapped in the dorsoventral plane. No mediolateral sprouting was seen into those areas of neuropil solely innervated by the test nerve. We conclude that intact myelinated primary afferents do have the capacity to collaterally sprout, but that any resultant somatotopic reorganization of central projections is limited to the dorsoventral plane. These changes may contribute to sensory hypersensitivity at the edges of denervated skin. J. Comp. Neurol. 380:95–104, 1997.

Null Mutations Lacking Substance: Elucidating Pain Mechanisms by Genetic Pharmacology

What can therefore be concluded from these studies? Knocking out the production or the action of substance P via the preprotachykinin A or NK1 receptor genes disturbs the reaction to somatic and visceral noxious stimuli but not in a universal or consistent manner, while most pharmacological studies have failed to show an action of NK1 receptor antagonists on normal cutaneous mechanical or thermal sensitivity. Substance P is not, therefore, the pain transmitter. What is its prime function, then? In the periphery, the role of substance P in neurogenic extravasation has been well defined, with significant reductions seen both with NK1 antagonists and in the knockouts. Because of the complexity of the phenotype of the knockouts and the difficulty of assaying central pain mechanisms, the role of substance P in synaptic transmission within the CNS remains somewhat elusive. One must begin to wonder whether we are asking the right questions or using appropriate assays—the role of substance P in pain has been tested genetically and pharmacologically using protocols designed to evaluate opiate or nonsteroidal anti-inflammatory type analgesics and not in studies where pain hypersensitivity after inflammation is a prominent feature. However, despite the fact that available clinical trial data are not encouraging, it may be premature to totally abandon NK1 receptor antagonists for pain treatment. Since C-fiber input to the CNS involves parallel transmitter action on multiple receptors, a polypharmacy approach might make more sense if one is targeting postsynaptic receptors. This could involve combinations of NK1, mGluR, and NMDA receptor antagonists together with opioids to improve analgesic efficacy.It is possible that substance P may be involved only in severe pain, being released in the spinal cord by massive amounts of tissue damage. Alternatively, substance P may play a nonessential role in the pathophysiology of pain, such that eliminating its action does not eliminate pain. Rather than signaling the presence or absence of noxious stimuli, it is possible that substance P, acting in parallel rather than serial synaptic information transfer, contributes to synaptic gain more than pain and that its action is more one of modulation than transmission.

DEAFFERENTATION IS INSUFFICIENT TO INDUCE SPROUTING OF A-FIBRE CENTRAL TERMINALS IN THE RAT DORSAL HORN

The mechanism by which A‐fibres sprout into lamina II of the dorsal horn of the adult rat after peripheral nerve injury, a region which normally receives input from noci‐ and thermoreceptive C‐fibres alone, is not known. Recent findings indicating that selective C‐fibre injury and subsequent degenerative changes in this region are sufficient to induce sprouting of uninjured A‐fibres have raised the possibility that the structural reorganisation of A‐fibre terminals is an example of collateral sprouting, in that deafferentation of C‐fibre terminals alone in lamina II may be sufficient to cause A‐fibre sprouting.