Autotomy behavior correlates with the DRG and spinal expression of sodium channels in inbred mouse strains.

Patients who have suffered nerve injury show profound inter-individual variability in neuropathic pain even when the precipitating injury is nearly identical. Variability in pain behavior is also observed across inbred strains of mice where it has been attributed to genetic polymorphisms. Identification of cellular correlates of pain variability across strains can advance the understanding of underlying pain mechanisms. Voltage-gated sodium channels (VGSCs) play a major role in the generation and propagation of action potentials in the primary afferents and are therefore of obvious importance for pain phenotype. Here, we examined the mRNA expression levels of the VGSC alpha-subunits Na(v)1.3, Na(v)1.5, Na(v)1.6, and Na(v)1.7, as well as the auxiliary VGSC-related molecule, Contactin. Dorsal root ganglia (DRG) and spinal cords from 5 inbred mouse strains with contrasting pain phenotype (AKR/J, C3H/HeJ, C57BL/6J, C58/J and CBA/J) were analyzed 7 days following sciatic and saphenous nerve transection. In the DRG, Na(v)1.6, Na(v)1.7 and Contactin were abundantly expressed in control animals. Following nerve injury, the residual mRNA levels of Na(v)1.6 (downregulated in two of the strains) correlated tightly to the extent of autotomy behavior. A suggestive correlation was also seen for the post-injury mRNA levels of Contactin (downregulated in all strains) with autotomy. Thus, our results suggest a contribution by DRG Na(v)1.6, and possibly Contactin to neuropathic pain in the neuroma model in mice.

The biochemical basis of the neurobehavioral abnormalities in the Lesch-Nyhan syndrome: a hypothesis.

Lesch-Nyhan syndrome (LNS) is a rare X-recessive disorder that leads to virtually complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Partial HPRT deficiency results in uric acid overproduction with subsequent hyperuricemia, nephrolithiasis, renal failure and gouty arthritis. In contrast, at complete HPRT deficiency, besides overproduction of uric acid neurological problems appear including spasticity, choreoathetosis, mental retardation, and compulsive self-mutilation. The cause for the uric acid overproduction has been clarified, but the connection between the enzyme deficiency and the neurological manifestations in LNS remains unclear. A hypothesis, which explains this relation, is proposed in the paper. The hypothesis has several important points most substantial of which is the accelerated biosynthesis of semiessential amino acid histidine that against the background of accelerated purine de novo biosynthesis results in 5-aminoimidazole-4-carboxamideribotide (AICAR) and histamine accumulation. The histamine and AICAR were determined to be the compounds that cause the neurobehavioral symptoms of LNS for several reasons. First, in the basal ganglia a balance between the direct (activating) and the indirect (inhibiting) pathways arising on the basis of the antagonistic and reciprocal dopamine-adenosine interactions normally exists. This balance can tonically regulate smooth voluntary movements and the activity of the thalamus, which, in turn, processes the afferent sensorimotor signals from the whole body to the all areas of the cerebral cortex and is concerned to modulate mental development and bring sensory information into awareness. Second, histamine is known to induce a selective damage in dopaminergic neurons inhibiting the direct dopaminergic pathway, which could lead to muscular rigidity, and slowness in initiating movements as well as tremor that are characteristic of Parkinsonism in LNS. Third, AICAribosid (AICAR breakdown product) is a potent adenosine A2a receptor antagonist inhibiting the indirect dopamine-adenosinergic pathway and, therefore, could be responsible for the choreoathetosis, dystonia and ballismus found in LNS. The excitatory-inhibitory disbalance in the basal ganglia could result in inadequate modification of the thalamus activity with subsequent mental retardation and symptoms that include the patients not being aware for their own bodies that could give rise to self-mutilation. Finally, a possibility for the creation of a new animal model that could exactly match the human LNS is proposed in the paper.

Spinal c-fos expression associated with spontaneous biting in a mouse model of dry skin pruritus.

As a model of dry skin pruritus in mice, one hind paw was treated twice daily with a mixture of acetone/diethylether/water (AEW); controls received water only. A protective collar prevented the animals from accessing the treatment area. At 16 days, the collar was removed and AEW-treated mice exhibited marked biting of the treated paw; the number and cumulative duration of bites was significantly greater than in controls. After 3 additional treatment days (collars intact), animals were perfused for c-fos immunohistochemistry. There was significantly more fos-like immunoreactivity in the ipsilateral lumbar spinal cord of AEW-treated animals, with the majority in superficial laminae. It is proposed that biting of the dry skin reflects pruritus, and that neurons predominantly in superficial laminae of the dorsal horn may signal itch sensation.

Spinal neurons involved in the generation of at-level pain following spinal injury in the rat.

Using a conjugate of substance P and the ribosome-inactivating protein saporin, neurons expressing the neurokinin-1 receptor in lamina I of the spinal cord were targeted to determine their role in the expression of a spontaneous pain behavior following intraspinal injections of quisqualic acid in the rat. Treatment was carried out at the time of injury in order to prevent the onset of the behavior, and following onset in order to evaluate the potential clinical utility of this intervention. Treatment at the time of injury resulted in significant decreases in onset-time and severity of pain behavior, while treatment at the time of onset led to a significant reduction of the spontaneous self-directed behavior. The results suggest that the substrate for at-level pain following spinal cord injury includes a population of spinal neurons expressing the neurokinin-1 receptor in the superficial laminae of the spinal cord.

Suppression of autotomy by N-methyl-D-aspartate receptor antagonist (MK-801) in the rat.

The effects of different doses and time of administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801) on the development of the autotomy (self-mutilation) were studied in the rats receiving dorsal root ganglionectomy (DRGn). The rats without any treatment and those treated with normal saline immediately after DRGn were the control groups. Three groups of rats were treated with 0.1, 0.5 or 1.0 mg/kg of MK-801 immediately after DRGn, and another three were treated with 1.0 mg/kg of MK-801 2, 4, or 7 days after DRGn. The behavioral observations of these rats were quantified using an autotomy grading scale ranging from 0 to 19, and the scores were compared among these groups. The rats in the control groups manifested autotomy from 5 to 17 days after DRGn and all of them (100%) attained the highest autotomy score. Lower doses (0.1 or 0.5 mg/kg) of MK-801 had no effect on the development of the autotomy. In contrast, higher dose (1.0 mg/kg) of MK-801 administered immediately after DRGn significantly suppressed the autotomy as compared to the control groups (P < 0.01) and only 17% of the rats in this group attained the highest score. The antagonistic effect was retained when the treatment of MK-801 was delayed to 2 days after DRGn, however, it disappeared when the treatment was delayed to 4 or 7 days after DRGn. Thus, the antagonistic effect of MK-801 on the autotomy induced by DRGn was dose-related and time-dependent. The main role of the NMDA receptor in the development of the autotomy was within several days after DRGn.

Nursing care of the self-mutilating patient.

Self-mutilative behavior is common among patients with multiple personality and other dissociative disorders. Nursing staff members face particular challenges in managing these patients because one act of self-mutilation can disrupt the entire inpatient milieu. The authors present an approach to nursing care that focuses on working with patients to understand and develop a specific plan to curtail the self-mutilative behavior.

D1 dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjected to neonatal dopaminergic denervation: implications for self-injurious behavior.

The present study examined the influences of dopamine (DA) receptor stimulation on enkephalin (Met5-enkephalin; ME) and tachykinin (substance P; SP) systems of basal ganglia of Sprague-Dawley rats, lesioned as neonates with 6-hydroxydopamine (6-OHDA). It has been proposed that the neonatal 6-OHDA-lesioned rat could serve as a model for the DA deficiency and self-injurious behavior (SIB) observed in the childhood neurological disorder. Lesch-Nyhan syndrome. In agreement with earlier work, the present study found that the neonatal 6-OHDA treatment at 3 days of age, reduced DA and caused an increase in ME and a decrease in SP content in the striatum and substantia nigra, when tested as adults. Administration of the DA precursor, L-dihydroxyphenylalanine (L-DOPA), to lesioned animals, induced SIB; increased DA and DOPAC levels; produced a greater decrease (-64%) in SP levels in the striatum and substantia nigra than was observed with lesion alone (-28%). The L-DOPA-induced decrease in SP levels and the SIB observed in the lesioned animals were blocked by pretreatment with the D1 receptor antagonist, SCH-23390. Moreover, administration of the D1 receptor agonist, SKF-38393, but not the D2 agonist, LY-171555, to lesioned animals mimicked the L-DOPA responses in all respects, except that the agonists did not alter DA or DOPAC levels. None of the DA agonists or antagonists treatments affected lesion-induced increase in ME levels in the striatum. These results indicate for the first time, that SIB precipitated by DA agonists in neonatal dopaminergic denervated animals, is associated with a marked and selective decrease in SP in the striatonigral SP neurons. This process has two components: (a) a retarded development of the SP system due to neonatal dopaminergic denervation: and (b) a depletion of the remaining SP, presumably by enhanced release due to D1 DA receptor-mediated activation of striatonigral SP neurons.

Dopamine deficiency in self-injurious behavior.

Based on the report that patients with Lesch-Nyhan Syndrome (LNS) have a central deficiency of dopamine similar in magnitude to that seen in Parkinsonism, the age at which dopaminergic neurons are disrupted was proposed to explain the differing symptoms observed in these two disorders. To investigate this hypothesis, brain dopaminergic neurons were lesioned in neonatal and adult rats with 6-hydroxy-dopamine (6-OHDA). Results demonstrated that neonatally lesioned rats had learning deficits and elevated levels of serotonin in the striatum--characteristics observed in LNS. Administration of L-dopa produced self-injurious behavior (SIB) in neonatally lesioned but not adult lesioned rats. Subsequent studies revealed that the SIB induced by L-dopa was dependent upon activation of D1 receptors. The elevated susceptibility of neonatally lesioned rats for SIB was demonstrated further by the enhanced occurrence of SIB when muscimol was administered into the substantia nigra reticulata (SNR). Other studies demonstrated that adenosine agonists could antagonize SIB, suggesting that the reduced adenosine observed in LNS may contribute to this symptom. The basic work being performed should be relevant to LNS and to other developmental disorders exhibiting SIB.

Autotomy and central nervous system neuropeptides after section of the sciatic nerve in rats of different strains.

Autotomy and the concentrations of beta-endorphin and Met-enkephalin in brain areas and the spinal cord were measured in Sprague Dawley, Wistar and Wistar Lewis rats thirty-five days after the section of one sciatic nerve. As expected, autotomy developed in Sprague Dawley and Wistar, but not in Wistar Lewis rats. In the Wistar Lewis, brain and spinal cord concentrations of Met-enkephalin increased, beta-endorphin concentrations were unchanged. In Wistar and Sprague Dawley rats the increase of Met-enkephalin was accompanied by a decrease of beta-endorphin. Administration of chlomipramine, a drug usually employed in the treatment of deafferentiation pain, normalized the concentrations of beta-endorphin in the Sprague Dawley and Wistar rats, and avoided the development of autotomy, while Met-enkephalin concentrations did never change. The data presented suggest a possible correlation between beta-endorphin and autotomy.

The serotonin hypothesis of (auto)aggression. Critical appraisal of the evidence.

Based on the relation found to exist between low CSF 5-HIAA and suicide attempt, in particular violent suicide attempt, both in depressed and in so-called nondepressed suicide attempters, the conclusion was drawn that decreased central 5-HT metabolism is related to (auto)aggression, rather than to depression. We challenged this conclusion and that for three reasons: Violent suicide attempt accumulates in certain types of depression making it impossible to conclude whether the biological variable relates to (auto)aggression or to that type of depression as such. Nondepressed suicide attempter is a diagnosis that should be based on presuicidal not on postsuicidal data, in order to avoid false-positive diagnoses. Suicide method is not a reliable index of seriousness of the attempt. Risk/rescue ratio should be used instead. Next the data are discussed that do support the hypothesis that diminished 5-HT metabolism in the brain is related to disregulation of aggression. Finally, the hypothesis is launched that both mood and aggression disorders are related to decreased 5-HT metabolism in the CNS. This would provide a biological explanation for the clinical observation that disorders in mood and in aggression often go hand in hand. Biological research of psychiatric disorders gains in informative value as the psychopathological analysis of the phenomena one studies is more comprehensive. Biological suicide research is no exception to this rule.

The biochemical basis of the behavioral disorder in the Lesch-Nyhan syndrome.

An inherited complete deficiency of hypoxanthine-guanine phosphoribosyltransferase in male children is associated with a severe neurological disorder characterized by chloroform and athetoid movements, hypertonicity, mental retardation, and self-injurious behavior. In the review that follows several possible mechanisms by which the enzyme defect may cause the CNS disorder are discussed. Current evidence suggests that the primary neural deficit in the Lesch-Nyhan syndrome is a deficiency of dopamine in the basal ganglia. It is argued that this neurochemical lesion results from a deficiency of purine nucleotides which impairs arborization of nigrostriatal neurons during perinatal development. Differences in the ontogenetic timing of the neurochemical lesion may be partly responsible for the different neurological symptoms displayed by persons afflicted with the Lesch-Nyhan and Parkinson's syndromes.

The possible participation of a dopaminergic system in mutilating behavior in rats with forelimb deafferentation.

Partial rhizotomy (section of dorsal roots C5 to Th 1 included) leads to abnormal mutilating behavior in the rat, presumably due to pain sensation in the deafferented limb. As dopamine (DA) has been shown to play a role in analgesia, destruction and stimulation of the ventral tegmental area (VTA) were used to check whether they induced an increase or a decrease in the mutilating behavior respectively. Destruction of DA neurons located in the VTA was performed by local administration of 6-hydroxydopamine whereas activation was achieved either by imposed electrical stimulation or by chronic oral administration of D-amphetamine sulfate. These 3 treatments accelerated the onset of the mutilating behavior and induced an extension of the mutilating wounds, D-amphetamine sulfate producing the most pronounced acceleration in their development. The results obtained after destruction of DA-VTA neurons fit well with the working hypothesis. The increase of the mutilating behavior rather than a decrease subsequent to the other treatments could have been caused by the hyperactivity and increase of chewing behavior induced by the less specific stimulating techniques.

Mechanism of excessive purine biosynthesis in hypoxanthine-guanine phosphoribosyltransferase deficiency.

Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-(14)C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol. In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-(14)C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of (14)C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does not contribute significantly to the formation of uric acid in either normal man or in patients with HG-PRTase deficiency.HG-PRTase was not completely absent in red blood cells from a boy with the Lesch-Nyhan syndrome; with hypoxanthine as substrate, the activity in erythrocyte hemolysates was 0.64% of normal values.