Neurotrophic factors and neuropathic pain.

Neuropathic pain is a debilitating consequence of nerve damage. Existing treatment is largely ineffective. Current models of neuropathic pain recognise the importance of ectopic activity in primary sensory neurones impinging on a sensitised central nervous system. Neurotrophic factors have been shown to be neuroprotective for damaged sensory neurones, providing a rationale for testing their effects in neuropathic pain states. Recent data have demonstrated potent analgesic effects of one factor (glial cell line-derived neurotrophic factor) in animal models of neuropathy, and implicated changes in sodium channel alpha-subunits in the generation of afferent ectopic activity. The new findings provide a rational basis for the use of neurotrophic factors as a novel therapeutic treatment for neuropathic pain states.

Effect of trap position, habitat, and height on the capture of pepper maggot flies (Diptera: Tephritidae).

Trapping results indicate that pepper maggot, Zonosemata electa (Say), flies occupy tree canopies adjacent to fields when not on host plants. Several in- and near-field trap positions were used to find a reliable monitoring system for adult pepper maggots. Traps baited with liquid ammonium hydroxide (Stills-style trap), hung in the canopy of trees on the edges of pepper fields, caught significantly more Z. electa flies than when positioned lower along the treeline or in the field. In a second experiment, significantly more pepper maggot flies were captured in sugar maples compared with choke cherry trees, which indicates a pest preference for certain nonhost habitats. The lowest trap height tested (2.1 m) failed to capture Z. electa flies in either tree species when the pest population level was low. These studies demonstrated that pepper maggot flies can be reliably detected with Stills-style traps positioned at approximately 6.4 m height within the canopy of sugar maple trees adjacent to pepper fields. Fruit oviposition scars also are useful site-specific indicators of pepper maggot presence/absence and may aid in determining if insecticide applications are necessary and in timing sprays.

Potent analgesic effects of GDNF in neuropathic pain states.

Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.

Intrathecally injected neurotrophins and the release of substance P from the rat isolated spinal cord.

The aim of this study was to investigate the effects of intrathecally delivered trophic molecules nerve growth factor (NGF), neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) on substance P (SP) release and content in the rat spinal cord and SP content in sciatic nerve. SP release was assayed with an in vitro dorsal roots-attached spinal cord preparation, in which the roots were stimulated at A- or C-fibre strength, and SP levels were measured by radioimmunoassay (RIA). NGF but not NT-3 and GDNF treatment caused a significant increase in basal SP outflow; NGF, NT-3 but not GDNF increased C-fibre stimulation-evoked SP release, and capsaicin superfusion-induced SP release. The increase in C-fibre stimulation-evoked SP release over basal outflow was greater in NGF- than NT-3-treated cords, and nociceptive threshold testing showed that intrathecal NGF, but not NT-3 or GDNF treatment was associated with thermal hyperalgesia. There was no detectable A-fibre stimulation-induced SP release from any group as well as no change in SP content in the sciatic nerve and spinal cord. Systemic treatment with the NGF-sequestering fusion protein trkA-IgG significantly inhibited electrically or capsaicin-evoked SP release without affecting basal outflow and SP content in spinal cord and sciatic nerve. These results suggest that: (i) NGF tonically regulates the central synaptic function of SP-containing primary afferents; (ii) increased SP-release from the spinal cord is not necessarily associated with behavioural hyperalgesia as in NT-3-treated rats there was increased SP release but no detectable hyperalgesia; and (iii) because A-fibre stimulation failed to increase SP release in any group, these neurotrophins are unlikely to be responsible for the de novo upregulation of SP in large afferents seen after peripheral inflammation or nerve injury.

The glial cell line-derived neurotrophic factor family receptor components are differentially regulated within sensory neurons after nerve injury.

Glial cell line-derived neurotrophic factor (GDNF) has potent trophic effects on adult sensory neurons after nerve injury and is one of a family of proteins that includes neurturin, persephin, and artemin. Sensitivity to these factors is conferred by a receptor complex consisting of a ligand binding domain (GFRalpha1-GFRalpha4) and a signal transducing domain RET. We have investigated the normal expression of GDNF family receptor components within sensory neurons and the response to nerve injury. In normal rats, RET and GFRalpha1 were expressed in a subpopulation of both small- and large-diameter afferents projecting through the sciatic nerve [60 and 40% of FluoroGold (FG)-labeled cells, respectively]. GFRalpha2 and GFRalpha3 were both expressed principally within small-diameter DRG cells (30 and 40% of FG-labeled cells, respectively). Two weeks after sciatic axotomy, the expression of GFRalpha2 was markedly reduced (to 12% of sciatic afferents). In contrast, the proportion of sciatic afferents that expressed GFRalpha1 increased (to 66% of sciatic afferents) so that virtually all large-diameter afferents expressed this receptor component, and the expression of GFRalpha3 also increased (to 66% of sciatic afferents) so that almost all of the small-diameter afferents expressed this receptor component after axotomy. There was little change in RET expression. The changes in the proportions of DRG cells expressing different receptor components were mirrored by alterations in the total RNA levels within the DRG. The changes in GFRalpha1 and GFRalpha2 expression after axotomy could be largely reversed by treatment with GDNF.