Recent evidence for activity-dependent initiation of sympathetic sprouting and neuropathic pain

Traumatic injury or inflammatory irritation of the peripheral nervous system often leads to persistent pathophysiological pain states. It has been well-documented that, after peripheral nerve injury or inflammation, functional and anatomical alterations sweep over the entire peripheral nervous system including the peripheral nerve endings, the injured or inflamed afferent fibers, the dorsal root ganglion (DRG), and the central afferent terminals in the spinal cord. Among all the changes, ectopic discharge or spontaneous activity of primary sensory neurons is of great clinical interest, as such discharges doubtless contribute to the develop-ment of pathological pain states such as neuropathic pain. Two key sources of abnormal spontaneous activity have been identified following peripheral nerve injury: the injured afferent fibers (neuroma) leading to the DRG, and the DRG somata. The purpose of this review is to provide a global account of the abnormal spontaneous activity in various animal models of pain. Particular attention is focused on the consequence of peripheral nerve injury and localized inflammation. Further, mechanisms involved in the generation of spontaneous activity are also reviewed; evidence of spontaneous activity in contributing to abnormal sympathetic sprouting in the axotomized DRG and to the initiation of neuropathic pain based on new findings from our research group are discussed. An improved understanding of the causes of spontaneous activity and the origins of neuropathic pain should facilitate the development of novel strategies for effective treatment of pathological pain.     

Chronic Constriction of the Sciatic Nerve and Pain Hypersensitivity Testing in Rats

Chronic neuropathic pain, resulting from damage to the central or peripheral nervous system, is a prevalent and debilitating condition, affecting 7-18% of the population^1,2. Symptoms include spontaneous (tingling, burning, electric-shock like) pain, dysaesthesia, paraesthesia, allodynia (pain resulting from normally non-painful stimuli) and hyperalgesia (an increased response to painful stimuli). The sensory symptoms are co-morbid with behavioural disabilities, such as insomnia and depression. To study chronic neuropathic pain several animal models mimicking peripheral nerve injury have been developed, one of the most widely used is Bennett and Xie''s (1988) unilateral sciatic nerve chronic constriction injury (CCI)³ (Figure 1). Here we present a method for performing CCI and testing pain hypersensitivity.CCI is performed under anaesthesia, with the sciatic nerve on one side exposed by making a skin incision, and cutting through the connective tissue between the gluteus superficialis and biceps femoris muscles. Four chromic gut ligatures are tied loosely around the sciatic nerve at 1 mm intervals, to just occlude but not arrest epineural blood flow. The wound is closed with sutures in the muscle and staples in the skin. The animal is then allowed to recover from surgery for 24 hrs before pain hypersensitivity testing begins.For behavioural testing, rats are placed into the testing apparatus and are allowed to habituate to the testing procedure. The area tested is the mid-plantar surface of the hindpaw (Figure 2), which falls within the sciatic nerve distribution. Mechanical withdrawal threshold is assessed by mechanically stimulating both injured and uninjured hindpaws using an electronic dynamic plantar von Frey aesthesiometer or manual von Frey hairs⁴. The mechanical withdrawal threshold is the maximum pressure exerted (in grams) that triggers paw withdrawal. For measurement of thermal withdrawal latency, first described by Hargreaves et al (1988), the hindpaw is exposed to a beam of radiant heat through a transparent glass surface using a plantar analgesia meter^5,6. The withdrawal latency to the heat stimulus is recorded as the time for paw withdrawal in both injured and uninjured hindpaws. Following CCI, mechanical withdrawal threshold, as well as thermal withdrawal latency in the injured paw are both significantly reduced, compared to baseline measurements and the uninjured paw (Figure 3). The CCI model of peripheral nerve injury combined with pain hypersensitivity testing provides a model system to investigate the effectiveness of potential therapeutic agents to modify chronic neuropathic pain. In our laboratory, we utilise CCI alongside thermal and mechanical sensitivity of the hindpaws to investigate the role of neuro-immune interactions in the pathogenesis and treatment of neuropathic pain.     

Social status, activity and preputial glands of wild and domestic house mice

Scent marking by deposition of urine, and the preputial glands, of adult, male, wild house mice, Mus mmmlus L., were studied and compared with those of an outbred domestic strain. The preputial glands of dominant wild mice were always heavier than those of subordinates. No dominance relationships could be established among the domestic mice. For study of scent marking each mouse was observed singly in a residential maze. Dominant wild mice marked more than the subordinates. The domestic mice scent-marked much less even than the subordinate wild mice. Subordinate wild mice spent less time than the dominant wild mice outside the nest; but the number of excursions outside the nest made by the subordinates resembled that of the dominants. Hence social status influenced the pattern of movements in a structured environment.     

A QUANTITATIVE ASSESSMENT OF DOMINANCE RELATIONS AMONG BOTTLENOSE DOLPHINS

Agonistic behavior of bottlenose dolphins was studied at Brookfield Zoo for nearly 4.5 yr, and dominance relationships were determined using a quantitative technique adapted from primate behavioral research. Dominance relations among dolphins were influenced by the gender of participants. Male dolphins were clearly and consistently dominant to females, and intersexual agonism occurred at moderate rates with seasonal peaks in spring and fall. Dominance relationships among female dolphins were age-ordered and stable, even though agonism among females did occur at uniformly low rates. In contrast, the two males had a changeable dominance relationship in which periods of stability and low-level agonism were interspersed with episodes of intense competition. Zoo-based research revealed patterns of behavior that conformed to current knowledge about bottlenose dolphin social structure. Moreover, research in a zoo setting facilitated development of a quantitative technique that can be used to assess cetacean dominance relationships in field research.     

Social dominance in female bighorn sheep

A group of six individually identified bighorn ewes (Ovis canadensis canadensis) in the Denver Zoo, Denver, Colorado, was studied to determine the existence of a dominance hierarchy. Using success in displacement interactions as an index to rank, a very linear, age-related hierarchy was found.     

一种刺激内脏大神经的慢性测痛方法

用聚四氟乙烯绝缘多股银丝作双极电极,埋置于左侧大内脏神经上,以刺激大内脏神经引起行为反应所需的最小电流强度作为内脏痛觉阈值。刺激参数为短串单相方波,串长500ms,波宽1ms,频率40Hz,强度为每隔5s递增约0.1mA,至出现行为反应时停止。30只家兔121次测试,内脏痛阈均值为1.16±0.056mA。在18只家兔中每只兔测定12次痛阈,其阈值相当稳定,波动在0.07mA 之间,用随机区组方差分析无显著意义。在14只家兔中静脉注射芬坦尼(20μg/kg),5min 后阈值升高显著,维持15min,其后渐趋恢复。作者认为,本方法可用于测定内脏痛阈的实验研究。