Abstract
It is without dispute that the treatment of neuropathic pain is an area of largely unmet medical need. Available analgesics, such as morphine, either have minimal effects in neuropathic pain patients, or are not always well tolerated due to concurrent adverse effects. The chronicity of neuropathic pain is thought to be related to many neurochemical changes in the dorsal root ganglia (DRG) and spinal cord, including a reduction in the retrograde transport of nerve growth factor (NGF). In this study, we have determined the ability of chronic intrathecal (i.t.) infusion of NGF to reverse neuropathic pain symptoms and to restore morphine’s effectiveness in an animal model of neuropathic pain. Seven days after sciatic nerve constriction injury, NGF was administered to the spinal cord by continuous infusion (125 ng/μl/h) via osmotic pumps attached to chronically implanted i.t. catheters. Spinal infusion of NGF did not affect the expression of tactile allodynia or thermal (hot) hyperalgesia in neuropathic rats, although it significantly increased cold water responses frequency at day 14. Following infusion of vehicle, i.t. morphine (20 μg) was ineffective in altering somatosensory thresholds in neuropathic rats. In contrast, morphine substantially attenuated the neuropathy-induced warm and cold hyperalgesia, as well as tactile allodynia, in neuropathic rats chronically infused with i.t. NGF. In addition, we demonstrate that i.t. morphine-induced antinociception was augmented by a cholecystokinin (CCK) antagonist in animals chronically infused with i.t. antibodies directed against NGF. We hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.
Highlights
IntroductionNeuropathic pain is a chronic debilitating condition that is characterized by its lancinating or continuous burning-type pain, and is typically associated with the occurrence of allodynia (pain resulting from normally innocuous stimuli) and/or hyperalgesia (increased sensitivity and exaggerated responses to painful stimuli)
Neuropathic pain is a chronic debilitating condition that is characterized by its lancinating or continuous burning-type pain, and is typically associated with the occurrence of allodynia and/or hyperalgesia
Post hoc comparisons (Wilcoxon signedrank test) on mechanical thresholds and cold water frequency of responses revealed that compared to baseline, vehicle-treated and nerve growth factor (NGF)-treated rats had significantly lower mechanical thresholds, and an increase in frequency of cold responses, on all test days following sciatic nerve injury, demonstrating the development of tactile allodynia and cold hyperalgesia (Fig. 1A,C)
Summary
Neuropathic pain is a chronic debilitating condition that is characterized by its lancinating or continuous burning-type pain, and is typically associated with the occurrence of allodynia (pain resulting from normally innocuous stimuli) and/or hyperalgesia (increased sensitivity and exaggerated responses to painful stimuli). Injury to the peripheral and central nervous systems can give rise to the development of neuropathic pain, which is considered to be inherently resistant to opioids (Arner and Meyerson, 1993; Max et al, 1988). It has been well established that nerve growth factor (NGF) has a role in the development and maintenance of neurons in the peripheral (Barde, 1989) and central (Shelton and Reichardt, 1986) nervous systems. NGF is synthesized in peripheral tissues and retrogradely transported to the cell bodies of sensory neurons (dorsal root ganglia, DRG) (Goedert et al, 1981). Once in the DRG, NGF exhibits a trophic effect on the regulation of substance P and calcitonin gene related peptide
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