Pain
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The L5 spinal nerve ligation model of neuropathic pain in rats has been proposed as a model for sympathetically maintained pain (SMP) based on the effects of surgical or chemical sympathectomy on nerve injury induced behavior. In an attempt to confirm that the lesion produces an animal model of SMP, surgical sympathectomies were independently conducted in two different laboratories (Johns Hopkins and University Kiel) using male Sprague-Dawley (n = 30) or Wistar rats (n = 14). The L5 spinal nerve was ligated or cut and ligated. ⋯ Experiments in Wistar and Sprague-Dawley rats yielded the same results. Potential reasons for the discrepancies between the present study and earlier reports are discussed. These results indicate that an L5 spinal nerve injury rat model is not a reliable model for SMP.
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The systemic administration of anti-nerve growth factor (NGF) antibodies can prevent local sensory hypersensitivity and block nociceptive fibers from sprouting into denervated adult rat skin. However, in the case of chronic constriction injury (CCI) in a rat, there is evidence that NGF reverses some effects of axotomy and alleviates thermal hyperalgesia. It is with this in mind that we investigated the influence of local anti-NGF and NGF on neuropathic pain and collateral sprouting caused by CCI. ⋯ The results show that the effect of anti-NGF is delayed at the onset, is short in duration, and is dependent on the dosage. However, anti-NGF but not NGF blocked collateral sprouting and decreased the severity of autotomy, suggesting that anti-NGF may be a better potential alternative analgesic for the treatment of neuropathic pain in humans. The different initiation times to abolish thermal hyperalgesia by anti-NGF (delayed onset) and NGF (early onset) suggests that alterations in neurotrophic factors contribute to the development of behavioral hyperalgesia via a complex mechanism in CCI rats.
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Trigeminal neuralgia is an example of an extreme form of neuropathic pain and continues to be a real therapeutic challenge. Although the pathophysiology of the disorder is uncertain, vascular compression of the trigeminal root resulting in damage to primary afferent neurons is thought to play a major role in the generation of pain. In the present study, we have used a recently developed rat model of trigeminal neuropathic pain, where the neuropathy is produced by a chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION), and for the first time studied the effects of various pharmacological treatments on this purely sensory model of neuropathic pain. ⋯ Repeated injections of baclofen (3 mg/kg s.c.) partially alleviated the mechanical allodynia-like behaviour without effects on rotarod performance. The partial anti-allodynic effect of a single injection (5 mg/kg) of baclofen, which was already accompanied by slight motor disturbances, could be antagonized by CGP35348, a selective GABA(B)-receptor antagonist. Functional deficits in the GABAergic system may play an important role in the pathogenesis of this purely sensory rat model of trigeminal neuropathic pain.
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Tactile allodynia and thermal hyperalgesia, two robust signs of neuropathic pain associated with experimental nerve injury, have been hypothesized to be mechanistically distinguished based on (a) fiber types which may be involved in the afferent input, (b) participation of spinal and supraspinal circuitry in these responses, and (c) sensitivity of these endpoints to pharmacological agents. Here, the possibility that nerve-injury induced tactile allodynia and thermal hyperalgesia may be mediated via different afferent fiber input was tested by evaluating these responses in sham-operated or nerve-injured (L5/L6) rats before or after a single systemic injection of resiniferatoxin (RTX), an ultrapotent analogue of the C-fiber specific neurotoxin, capsaicin. Tactile allodynia, and three measures of thermal nociception, tail-flick, paw-flick and hot-plate responses, were determined before and at various intervals for at least 40 days after RTX injection. ⋯ The hypothesis that tactile allodynia may be due to inputs from large (i.e. A beta) afferents offers a mechanistic basis for the observed insensitivity of this endpoint to intrathecal morphine in this nerve-injury model. Further, these data suggest that clinical treatment of neuropathic pains with C-fiber specific agents such as capsaicin are unlikely to offer significant therapeutic benefit against mechanical allodynia.
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The development of alpha-adrenergic sensitivity in cutaneous nociceptors has been postulated as a mechanism for sympathetically maintained pain (SMP). In order to characterize the adrenergic receptors involved, we investigated the effects of intraplantar administration of alpha1-(prazosin) and alpha2-(yohimbine) adrenergic antagonists and systemic injection of phentolamine, a non-specific alpha-adrenergic blocker, on allodynic/hyperalgesic behavior in an animal model thought to mimic SMP in humans. Peripheral neuropathy in rats was induced by tight ligation of the L5/L6 spinal nerves. ⋯ Intradermal administration of yohimbine or prazosin did not significantly alleviate mechanical hyperalgesia in L5/L6 ligated animals. Also systemic administration of phentolamine (1 and 5 mg/kg) did not alleviate the increased incidence of paw withdrawal in L5/L6 spinal nerve ligated animals. These results suggest that an alpha adrenergic interaction between sympathetic efferent and somatic afferent fibers does not play a critical role for the maintenance of mechanical hyperalgesia in this model for neuropathic pain.