Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections

Abstract

Peripheral nerve injury produces signs of neuropathic pain including tactile allodynia and thermal hyperalgesia, sensory modalities which may be associated with different neuronal pathways. Studies of spinally-transected, nerve-injured rats have led to suggestions that thermal hyperalgesia may be mediated predominately through local spinal circuitry whereas ascending input to supraspinal sites is critical to the manifestation of tactile allodynia. Here, the nature of ascending spinal input mediating tactile allodynia was explored using selective spinal lesions. Male Sprague-Dawley rats received L(5)/L(6) spinal nerve ligation (SNL) and ipsilateral or contralateral (relative to the SNL side) lesions including spinal hemisections and bilateral and unilateral dorsal column lesions. The rats were maintained in a sling and monitored for tactile allodynia by measuring withdrawal thresholds to probing with von Frey filaments 24 h after the hemisection. Rats receiving dorsal column lesions demonstrated no motor deficits while rats receiving spinal hemisection showed paralysis of the paw which nevertheless responded to strong noxious stimulation. Spinal hemisection ipsilateral, but not contralateral, to SNL completely abolished tactile allodynia while maintaining spinal nocifensive reflexes to noxious pinch. Bilateral and ipsilateral dorsal column lesions blocked tactile allodynia while contralateral dorsal column lesions did not. Administration of lidocaine into the nucleus gracilis ipsilateral to SNL also blocked tactile allodynia, but did not alter thermal hyperalgesia in SNL rats or increase thermal nociceptive responses in sham-operated rats. Lidocaine microinjected into the contralateral nucleus gracilis produced no changes in responses to tactile or thermal stimuli in either group. These results indicate that tactile allodynia after peripheral nerve injury is dependent upon inputs to supraspinal sites. Furthermore, it is apparent that afferent signals interpreted as tactile allodynia course through the ipsilateral dorsal columns and are relayed through the nucleus gracilis. This neuronal pathway is consistent with the interpretation that tactile allodynia pursuant to peripheral nerve injury is transmitted to the central nervous system by means of large diameter, myelinated fibers.

Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor

“…The known projections of these fibers to the brainstem, along with the observations of plasticity at levels as far rostral as the midbrain after injury to peripheral nerves (Kovelowski et al, 2000), point to a role of supraspinal sites in the nerve injury-induced pain state. This concept is supported by various lesion studies of ascending pathways (Houghton et al, 1999;Sun et al, 2001) as well as by the emergence of evidence of the critical importance of descending pain facilitation pathways in nerve injury-induced pain. Specifically, blockade of nerve injuryinduced pain is seen after RVM microinjection of lidocaine (Pertovaara et al, 1996;Kovelowski et al, 2000) as well as by lesions of the DLF .…”

“…Manipulations designed to interfere with ascending, large-fiber projections to brainstem nuclei, including spinal transection, ipsilateral and contralateral hemisections, and selective lesions of the ipsilateral or contralateral (relative to the side of peripheral nerve injury) dorsal columns block nerve injury-induced pain (Bian et al, 1998;Sung et al, 1998;Sun et al, 2001). Lidocaine injection into the ipsilateral (relative to the side of peripheral nerve injury), but not contralateral, nucleus gracilis also blocks nerve injury-induced pain (Sun et al, 2001). These studies support a role for central processes in the mediation of experimental neuropathic pain.…”

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

“…It is thought that this enhanced responsivity of sensory neurons in the spinal dorsal horn, termed central sensitization (Ji and Woolf, 2001;Sotgiu and Biella, 2000) or long term potentiation (Ji et al, 2003;Sandkuhler and Liu, 1998), contributes to neuropathic pain by facilitating and prolonging transmission of nociceptive information to supraspinal pain networks Sun et al, 2001). …”

Changes in calcitonin gene-related peptide expression following joint immobilization in rats

“…This observation suggests that central changes as well as local peripheral changes are implicated in immobilization-related pain. It is well known that intense nociceptive stimulation (e.g., inflammation, nerve injury and cancer) alters the character of neurons in the central nervous system [1,7,28] and these alterations are considered to be the cause of allodynia and hyperalgesia [22,24]. However, it remains unclear how these central neuronal changes occur under conditions of sensory input deprivation (long-term immobilization).…”