Chronic parasite infection in mice induces brain granulomas and differentially alters brain nerve growth factor levels and thermal responses in paws

Schistosoma mansoni infection, both in humans and in animal models, is known to induce granulomas in the liver and intestine. It has also been reported that in humans the eggs of this parasite can reach the brain, causing psychiatric and neuropathological disorders. Whether this also occurs in rodents is unknown. To answer this question, mice were infected with this parasite and the central nervous system (CNS) examined at various time intervals. The results show that schistosomiasis induced granulomas in several regions of the CNS and increased nerve growth factor (NGF) levels in the cortex, hypothalamus and brain stem, but not in the hippocampus. The infection also caused paw hyperalgesia, as determined by the hot-plate test, and a local increase in NGF, but not in substance P. These findings indicate that the murine model of infection can be used for studying mechanisms leading to human neuroschistosomiasis and suggest that the neuropathological disorders and the sensory deficits observed in human schistosomiasis are associated with impaired levels of NGF in the peripheral and central nervous system. Received: 18 January 1996 / Revised, accepted: 16 April 1996     

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)     

压迫及非压迫因素在实验性神经根性疼痛中的作用

目的：探讨压迫及非压迫因素在实验性椎间盘源性神经根性疼痛中的作用。方法：取大鼠白体脊椎关节突修剪后放置在L5神经根下．造成对L5神经根的直接压迫（压迫组）；取大鼠白体尾椎椎间盘组织无压迫下放置在L5神经根表面（非压迫组）：同时设立对照组。术后不同时间点测定各组大鼠后足底机械刺激疼痛阈值的变化。结果：压迫组与非压迫组大鼠后足底均产生了一个长时程机械刺激疼痛阈值的降低；与压迫组相比．非压迫组大鼠术后1天就开始出现了疼痛阈值降低（P〈0．05），明显早于压迫组大鼠，并且疼痛阈值降低更加显著：而压迫组大鼠术后1周时才出现明显的疼痛阈值降低（P〈0．05）。对照组大鼠疼痛阈值没有发生明显的改变。结论：尽管压迫和非压迫因素都参与椎间盘源性神经根性疼痛的发生．但二者作用的时间不同＋在椎间盘突出的早期阶段非压迫因素可能在疼痛中起着重要的作用：随后压迫因素可能逐渐成为致痛的主因。     

Analgesic actions of dynorphin A(1–13) antiserum in the rat brain stem

This study was performed to evaluate the effects of dynorphin A(1–13) antiserum when microinjected into an active hyperalgesic region within the rat brain stem. When administered within the dorsal posterior mesencephalic tegmentum (DPMT) of intact conscious rats, dynorphin A(1–13) antiserum produced rapid onset and persistent prolongation of a low intensity thermally evoked tail avoidance response (LITETAR). These analgesic actions of the dynorphin A(1–13) antiserum appeared to be dose dependent. These studies support previous hypotheses about the existence of tonically active brain stem opioid hyperalgesic processes. Further, the results provide indirect evidence for a potential role of brain stem dynorphin(s) in facilitating pain.     

Illness-induced hyperalgesia is mediated by spinal neuropeptides and excitatory amino acids

The spinal cord dorsal horn contains neural mechanisms which can greatly facilitate pain. We have recently shown that ‘illness’-inducing agents, such as intraperitoneally administered lipopolysaccharide (LPS; bacterial endotoxin), can produce prolonged hyperalgesia. This hyperalgesic state is mediated at the level of the spinal cord via activation of the NMDA-nitric oxide cascade. However, prolonged neuronal depolarization is required before such a cascade can occur. The present series of experiments were aimed at identifying spinal neurotransmitters which might be responsible for creating such a depolarized state. These studies show that LPS hyperalgesia is mediated at the level of the spinal cord by substance P, cholecystokinin and excitatory amino acids acting at non-NMDA sites. No apparent role for serotonin or kappa opiate receptors was found.     

Sensitization of nociceptive cutaneous nerve fibers from the rat's tail by noxious mechanical stimulation

Summary This single fiber study on rat tail nerve afferents attempts to establish a peripheral neural correlate for the hyperalgesia to mechanical stimulation which follows injury to the skin. Mechano-heat sensitive C fibers (MH-C or polymodal nociceptors) and high-threshold mechanoreceptive A delta fibers (HTM-A delta) were examined with a series of constant noxious pressure stimulations (4-6-8-4 N on 25 mm², 120 s each, 5 min intervals). These injurious stimuli were either directed to the most sensitive spot of the receptive fields (central stimulation) or closely outside their borders (1–5 mm). With this protocol no clear sensitization was seen in MH-C fibers apart from a stronger dynamic response to central stimulation in some of them. In contrast, most HTM-A delta units, irrespective of the site of noxious stimulation, developed spontaneous activity, lowering of their von Frey thresholds and expansion of their receptive fields. All HTM-A delta units responded to outside stimulation: upon the first stimulus (4 N) there was a delayed discharge of continuously increasing frequency (recruited response), but the onset of the last stimulation (4 N repeated) evoked vigorous dynamic responses in many fibers. The recruitment of HTM-A delta nociceptor activity may contribute to post-injury hyperalgesia to mechanical stimulation and it may counteract adaptation of the single afferent fiber during prolonged noxious influence.On leave from the Laboratoire de Physiologie, Faculté de Médecine Lyon-Sud, Chemin du Petit Revoyet, F-69600 Ouillins, France     

Desensitization to substance P following intrathecal injection

Summary The intrathecal injection of substance P (SP) (2.5–15 g) has been shown to produce hyperalgesia in the rat tail flick test. Repeated injection of SP (7.5 or 15 g) or pretreatment with two of these doses produces desensitization to this hyperalgesic response. Desensitization is doserelated with respect to degree and duration. This phenomenon is relatively specific because the hyperalgesic response to methysergide, a serotonin receptor antagonist, is unaffected, while that produced by phentolamine, an adrenergic receptor antagonist, is much less affected than that of SP. Pretreatment with a desensitizing regimen of SP potentiates the antinociceptive effect of morphine and baclofen when they are tested immediately after the regimen but if a 30 min delay is permitted, an inhibition of their effects is observed. These results support the notion that the spinal antinociceptive effect of morphine and baclofen is due to an interaction with SP mechanisms in the spinal cord, the nature of which may be more complex than is presently understood. Desensitization produces no change in baseline responsiveness in the tail flick test. This suggests that the hyperalgesic response to SP is due either to an action at a site other than the primary afferent synapse, or if it is at this site either compensatory mechanisms occur or SP is not the primary determinant of tail flick latency but may play a modulatory role.     

Description of a short-term Taxol-induced nociceptive neuropathy in rats

This work describes a new animal model of neuropathic pain produced by the single intraperitoneal administration of Taxol (32 mg/kg) to male Sprague-Dawley rats. During the course of the experiment, the clinical status of the rats remained satisfactory and motor function was not altered. A number of classical behavioural tests of nociception as well as histological and electrophysiological investigations were performed. Taxol administration produced an important and rapidly developing mechanical hyperalgesia, a thermal hypoalgesia but no mechanical or thermal allodynia. Degenerative changes were observed in the sciatic nerve, the nerve fibres in the paw subcutaneous tissue and in the lumbar spinal cord. When Taxol or vehicle (a mix of Cremophor and ethanol) were repeatedly injected once a week for 5 weeks, similar nociceptive disorders were observed in addition to a decrease in peripheral nerve conduction velocity. The selective dysfunction of high-diameter myelinated fibres observed after one single administration of Taxol (32 mg/kg) may be attributable to paclitaxel-induced neuropathy, however other mechanisms causing neurochemical dysfunction must also be involved.     

A possible role for nerve growth factor in the augmentation of sodium channels in models of chronic pain

Inflammation induces an upregulation of sodium channels in sensory neurons. This most likely occurs as a result of the retrograde transport of cytochemical mediators released during the inflammatory response. The purpose of this study was to determine the effect of the subcutaneous administration of one such mediator, nerve growth factor (NGF), on the production of sodium channels in neurons of the rat dorsal root ganglion. For this, hindpaw withdrawal from either a thermal or mechanical stimulus was measured in rats at selected intervals for up to 2 weeks following injections of NGF. Sodium channel augmentation was then examined in dorsal root ganglia using site-specific, anti-sodium channel antibodies. Both thermal and mechanical allodynia was observed between 3 and 12 h post-injection. The hyperalgesic response returned to baseline by approximately 24 h post-injection. Sodium channel labeling was found to increase dramatically in the small neurons of the associated dorsal root ganglia beginning at 23 h, reached maximum intensity by 1 week, and persisted for up to 3 months post-injection. Pre-blocking NGF with anti-NGF prevented the NGF-induced decrease in paw withdrawal latencies and significantly reduced the intensity of sodium channel labeling. The results indicate that NGF is an important mediator both in the development of acute hyperalgesia and in the stimulation of sodium channel production in dorsal root ganglia during inflammation.