精神分裂症患者性激素水平动态观察

对９０例精神分裂症男性病人做了性激素水平的动态变化测定，并与一组正常人（３３例男性）进行了比较，研究结果显示，病人组疗后睾酮（Ｔ）水平显著低于疗前，其变化与疗后简明精神病量表（ＢＰＲＳ），阴性症状量表（ＳＡＮＳ），阳性症状量表（ＳＡＰＳ）亦显著低于疗前，均有密切关系，病人组疗前和疗后Ｔ均显著低于正常对照组，而未婚者疗后促卵泡激素（ＦＳＨ）水平又显著低于已婚和离婚，丧偶者。     

Additional evidence for the involvement of the basal ganglia in formalin-induced nociception: the role of the nucleus accumbens

Identification of the brain areas that contribute to pain is an essential undertaking towards understanding persistent pain. Areas of the basal ganglia have been proposed to play important roles in nociception as previous studies have determined the involvement of the substantia nigra pars compacta and the dorsolateral striatum in pain. The purpose of the present study was therefore to expand upon these findings by determining the involvement of other areas of the basal ganglia such as the nucleus accumbens shell and core in formalin-induced nociception. It was found that injection of a local anaesthetic (bupivacaine) into the nucleus accumbens shell had no effect on formalin-induced nociception. However, injection into the nucleus accumbens core enhanced formalin-induced nociception. These results implicate the nucleus accumbens in the processing of pain and provide additional evidence for the involvement of the basal ganglia and possibly dopamine in pain.     

Differential effects of trigeminal tractotomy on Aδ- and C-fiber-mediated nociceptive responses

In this study we have tested in the rat, whether trigeminal tractotomy, which deprives the spinal trigeminal nucleus caudalis (Sp5C) of its trigeminal inputs, affected differentially nociceptive responses mediated by C- vs. Aδ-nociceptors from oral and perioral regions. Tractotomy had no effect on the threshold of the jaw opening reflex, induced by incisive pulp stimulation (Aδ-fiber-mediated), but blocked the formalin response (mainly C-fiber-mediated). These results suggest that nociceptive responses mediated by trigeminal C-fibers completely depend on the integrity of the Sp5C, while intraoral sensations triggered Aδ-fibers (especially of dental origin) are primarily processed in the rostral part of the spinal trigeminal nucleus.     

Repeated nociceptive stimulation induces different behavioral and neuronal responses in intact and gonadectomized female rats

Tissue damage induces acute pain but also long-term central modifications that can affect the behavioral and neuronal responses to a second painful stimulus. To study the effects of female gonadal hormones on the responses to repetition of a nociceptive stimulus, we subjected adult female rats to the formalin test. Three weeks after gonadectomy (GDX) or sham-surgery (INT), animals were randomly divided into groups to be left in the home cage as controls (HC) or to be exposed to Sham (S) or Formalin (F) stimuli (s.c. formalin injection, 50 microl, 5%, in the dorsal hind paw) in the subsequent 2 weeks (Trial 1; Trial 2). The resulting groups were: INT or GDX SS (Sham-Sham), SF (Sham-Form) and FF (Form-Form). During Trial 1, licking duration was longer in the INT-FF group than in GDX-FF; during Trial 2, there was no difference between the two groups due to the decrease in INT-FF alone. c-Fos expression, determined in the arcuate nucleus of the hypothalamus in the same animals 1 week after the last formalin test, was higher in GDX than INT animals; moreover, while in INT rats, c-Fos was higher in the formalin-injected animals (SF and FF) than in HC, in GDX, it did not differ among groups. These results show that female gonadal hormones affect the behavioral and neuronal responses to repeated nociceptive stimulation, indicating a possible role of ovarian hormones in determining sex differences in pain.     

Antisense knockdown of spinal-mGluR1 reduces the sustained phase of formalin-induced nociceptive responses

To examine the role of mGluR1 (a subunit of the group I metabotropic glutamate receptor) in the nociceptive responses of rats following a subcutaneous injection of formalin into the plantar surface of the hind paw, we delivered antisense oligonucleotides (ODNs) against mGluR1 into the rat lumbar spinal cord (L3–L5) intrathecally using an HVJ–liposome-mediated gene transfer method. Rats treated with a single injection of mGluR1 antisense ODNs into the intrathecal space of the lumbar spinal cord showed a marked reduction of the early-sustained phase of formalin-induced nociceptive responses, but not of their acute phase. The reduction of nociceptive behavioral responses became apparent at day 2 after the antisense treatment and lasted for 2 days. This corresponded to a long-lasting down-regulation (46%) of mGluR1 expression in the lumbar cord. This down-regulated mGluR1 was observed at day 2 and persisted until day 4 after the intrathecal infusion of mGluR1 antisense ODN. In contrast, rats treated with mGluR1 sense or mismatch ODNs showed none of these changes. These results suggest that mGluR1 may play a crucial role in the sustained nociception of formalin-induced behavioral responses.     

Inhibition of platelet-activating factor receptors in hippocampal plasma membranes attenuates the inflammatory nociceptive response in rats

Evidence suggests that platelet-activating factor (PAF) is a mediator in inflammatory-based pain. Using the biphasic formalin model in rats, we recently demonstrated that PAF antagonists which were selective for either intracellular or plasma membrane PAF receptors decreased the late-phase of the nociceptive response. Inasmuch as both of the PAF antagonists previously used were administered systemically, and reportedly are able to cross the blood-brain barrier, the anatomic locations at which PAF affects pain processing remained to be elucidated. Since PAF is required for hippocampal-dependent memory consolidation, and since the hippocampus has been shown to mediate the late-phase of formalin-induced nociception, the present study investigated the effects on nociception of administration of PAF antagonists within the hippocampus, and of using agents specific for either plasma membrane (BN 52021) or intracellular (BN 50730) PAF binding sites. Intrahippocampal injections of BN 52021 decreased the late-phase of the nociceptive response in a concentration-dependent manner. In contrast, intrahippocampal administration of BN 50730 had no effect on inflammatory nociception. These findings suggest that hippocampal plasma membrane PAF receptors, but not intracellular PAF binding sites, mediate tonic inflammatory pain processing in rats.     

Corpus callosum: ovarian hormones and feminization

The rat's corpus callosum is sexually dimorphic with the male's being larger. This difference appears to depend in part on the neonatal presence of testosterone in the male and ovarian hormones in the female. To further investigate the possibility that ovarian hormones participate in the differentiation of the rat's callosum, females received one of the following treatments on postnatal day 8, 12 or 16: (1) ovariectomy (Ovx); (2) 1 mg of testosterone propionate (TP); or (3) sham surgery. All animals were handled daily from birth until weaning. They were sacrificed at 110 days and a mid-sagittal section of the callosum was obtained. From this section measures of callosal area, perimeter, length, and 99 widths were derived. Widths were averaged into 7 factors as defined by prior factor analysis. Ovariectomy, whether on day 8, 12 or 16, enlarged callosal area and 3 of the callosal width factors. TP had no effect on any callosal variable when administered on day 8, 12 or 16. A comparison of control males and females replicated our prior findings of sexual dimorphism. We conclude that ovarian hormones act to feminize the female callosum, and that their removal results in defeminization. Furthermore, the fact that ovariectomy was effective as late as day 16, while TP treatment on day 8 or later had no effect, suggests that masculinization and feminization of this structure constitute separate processes with distinct sensitive periods.     

Antisense oligonucleotides to N-methyl-D-aspartate receptor subunits attenuate formalin-induced nociception in the rat

Noxious peripheral stimuli increase the sensitivity of central nociceptive neurons to subsequent noxious stimuli. This occurs in part through activation of spinal N-methyl-D-aspartate (NMDA) receptors. These receptors are heteromeric complexes of NMDA-R1 and NMDA-R2 A--D subunits. NMDA-R1 is necessary for the formation of functional NMDA receptors whereas the R2 subunits (A-D) modify the properties of the receptor. However, the role of the various receptor subtypes in nociception has not been established. In this study, we used intrathecally administered phosphodiester antisense oligonucleotides (ODEs) to examine the role of the NMDA-R1, NMDA-R2C and NMDA-R2D subunits in the mediation of formalin-induced nociception in the rat. The antisense ODEs against the NMDA-R1 and NMDAR-2C subunits reduced nociceptive behaviors whereas the corresponding sense ODEs had no effect. In contrast, nociception was unaffected by the antisense ODE to NMDAR-2D. Using an RNase protection assay, we also found that each antisense ODE selectively decreased the level of the corresponding mRNA in the lumbar spinal cord but that the sense ODEs had no such effect. Accordingly, these data provide evidence that the R1 and R2C subunits, but not R2D, of the NMDA receptor participate in the development of formalin-induced nociception.     

Prenatal stress alters time characteristics and intensity of formalin-induced pain responses in juvenile rats

Previous studies found that stressful events during pregnancy can alter the offspring's pain sensitivity to the phasic nociceptive stimuli. The present data constitute the first demonstration of the consequences of prenatal stress to formalin-induced pain in juvenile rats. Injection of formalin into a hind paw of a 25-day-old rat that had not been stressed prenatally produced the typical biphasic specific nociceptive behavioral response consisting of an early short phase lasting 1-4 min followed by a second prolonged phase (12-24 min). Between them there was an interphase that lasted 6-9 min during which the specific behaviors were not shown. This period is generally considered to be a period of inactivity. Prenatally stressed rat pups showed significant increase in flexing+shaking behaviors and in the duration of the second phase of formalin-induced pain in flexing+shaking and licking behaviors and decrease of the duration of the interphase. Disinhibition of the pain behaviors during the interphase was greatly more pronounced in female than in male rats. Sex differences indicate increased vulnerability of inhibitory processes to prenatal stress in females compared with males. These data also underline the importance of understanding the nature of the interphase and provide data on the mechanisms that underlie that component of the formalin test.     

The effect of systemic cocaine on spinal nociceptive reflex activity in the rat

In the anesthetized rat, cocaine (25 mg/kg i.p.), enhanced the frequency potentiation of nociceptively evoked polysynaptic discharges but did not affect the polysynaptic reflex discharge to single nociceptive stimuli or the habituation of this reflex to repetitive pinch stimuli. The non-nociceptive, short-latency reflex discharge was suppressed for 10-15 min after cocaine administration. The neurogenic extravasation response to antidromic cutaneous C-fiber stimulation was unaffected by cocaine. These findings suggest that systemic cocaine, in doses analgesic for the rat, does not suppress spinal nociceptive reflexes.     

Effects of neurotoxic destruction of descending noradrenergic pathways on cannabinoid antinociception in models of acute and tonic nociception

The effects of neurotoxic destruction of catecholaminergic projections to the spinal cord on cannabinoid antinociception were examined in models of acute and tonic nociception. High performance liquid chromatography was used to quantify monoamine levels in sham-operated and lesioned rats. Intrathecal administration of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) induced a selective depletion of norepinephrine (by approximately 85% of control) in rat lumbar spinal cord without altering levels of dopamine or serotonin. By contrast, brain levels of monoamines did not differ in sham-operated and lesioned rats. Pain behavior was similar in sham-operated and lesioned rats receiving vehicle in models of both acute and tonic nociception. The cannabinoid agonist WIN55,212-2 (5 or 10 mg/kg, i.p.) produced antinociception in the tail-flick test in sham-operated rats. The antinociceptive effect of WIN55,212-2 was attenuated relative to control conditions in rats depleted of spinal norepinephrine. WIN55,212-2 suppressed tonic pain behavior in the formalin test in sham-operated rats during phase 2 (15-60 min post formalin) of nociceptive responding. By contrast, in lesioned rats, WIN55,212-2 suppressed pain behavior during phase 1 (0-9.9 min) and phase 2A (10-39.9 min), but not during phase 2B (40-60 min). The cannabinoid agonist suppressed formalin-evoked Fos protein expression, a marker of neuronal activity, in the lumbar dorsal horn of sham-operated rats, but no suppression was observed in lesioned rats. The number of formalin-evoked Fos-like immunoreactive (FLI) cells was greater in lamina I and II of lesioned rats relative to sham-operated rats. These data indicate that the suppressive effect of the cannabinoid on formalin-evoked Fos protein expression in the superficial dorsal horn was attenuated following destruction of descending noradrenergic pathways. Our data are consistent with the hypothesis that cannabinoids produce antinociception, in part, by modulating descending noradrenergic systems and support a differential involvement of noradrenergic projections to the spinal cord in cannabinoid modulation of acute versus tonic nociception.     

Sex-related effects on behaviour and β-endorphin of different intensities of formalin pain in rats

The effects of two intensities of formalin on behaviour and β-Endorphin (β-EP) concentration in the brain and pituitary were studied in male and female rats. The animals were familiarized with the Hole-Board apparatus for 3 days, and then, after a subcutaneous injection of formalin (50 μl, 0.1 or 10%) or Sham-injection (Control) in the hindpaw, they were tested in the Hole-Board for 60 min. Licking, Flexing and Paw-Jerk of the injected limb were recorded. β-EP concentration was determined in the hypothalamus (HYP), the periaqueductal gray matter (PAG), the anterior pituitary (AP) and the neurointermediate lobe (NIL). Licking and Flexing durations were greater in females than males only with formalin 10%. Sex differences in β-EP concentration between the Control groups were found in all tissues except the HYP; β-EP levels were higher in females in the PAG and NIL, but greater in the AP in males. β-EP concentration increased in males in the HYP and NIL with formalin 10%; in females, a decrease was found in the HYP with formalin 0.1%. The present results suggest that: (a) there are differences between males and females in the responses to formalin pain, and the nature (pattern and duration) of the sex differences varies according to the pain intensity; (b) there are differences in β-EP concentration between the two sexes in control animals, and male and female rats also exhibit differences in the modifications of β-EP in response to formalin-induced pain.     

Developmental sex differences in glutamic acid decarboxylase (GAD65) and the housekeeping gene, GAPDH

Previous work has demonstrated that the GABAergic system is involved in sexual differentiation of the rodent hypothalamus. The present study was designed to further examine this involvement by investigating developmental sex differences in GAD₆₅ protein levels in hypothalamic and extrahypothalamic brain regions known to be sexually dimorphic in adulthood. Brain nuclei were micro-dissected and GAD₆₅ protein levels were quantified using western immunoblotting. Sex differences in levels of GAD₆₅ were found in the dorsomedial nucleus and preoptic area of the hypothalamus and also the medial amygdaloid nucleus and CA1 subfield of the hippocampus. Unexpectedly, there were sex differences in protein levels of the housekeeping gene, GAPDH, cautioning against the use of GAPDH for standardizing protein samples during western immunoblotting.     

Intrathecal xenogeneic chromaffin cell grafts reduce nociceptive behavior in a rodent tonic pain model

Adrenal medullary chromaffin cells synthetize and secrete a combination of pain-reducing neuroactive compounds including catecholamines and opioid peptides. Previous reports have shown that implantation of chromaffin cells into the spinal subarachnoid space can reduce both acute and chronic pain in several animal models. We recently demonstrated that human chromaffin cell grafts in the cerebrospinal fluid (CSF) could alleviate intractable cancer pain after failure of systemic opiates. However, wider application of this approach was limited by the limited availability of allogeneic donor material. Alternatively, chromaffin cells from xenogeneic sources such as bovine adrenal medulla were successful in the experimental treatment of pain, but recent concern over risk of prion transmission precluded use of bovine grafts in human clinical trials. The objective of the present study was to investigate the possibility of developing a new xenogeneic porcine source of therapeutic chromaffin cells because this strategy is currently considered the safest for transplantation in man. In the present study, we report the isolation and the characterization of primary porcine chromaffin cells (PCC) compared to bovine cells. We show, for the first time, that these cells grafted in the rat subarachnoid space can attenuate pain-related behaviors as assessed by the formalin test, a model of tonic pain. Moreover, in addition to behavioral studies, immunohistochemical analysis revealed robust survival of chromaffin cells 35 days after transplantation. Taken together, these results support the concept that porcine chromaffin cells may offer an alternative xenogeneic cell source for transplants delivering pain-reducing neuroactive substances.     

The involvement of dopamine in nociception: the role of D1 and D2 receptors in the dorsolateral striatum

Determination of the neuroanatomical and neurochemical factors that contribute to nociception is an essential element in the study and treatment of pain. Several lines of evidence have implicated nuclei and neurotransmitters within the basal ganglia in nociception. For example, previous studies have shown that dopamine receptors in the striatum are involved in acute nociception, however, it remains to be determined if dopamine receptors in the dorsolateral striatum are involved in persistent nociception. The purpose of the present study was therefore to determine whether activation or antagonism of dopamine receptors in the dorsolateral striatum influences the nociceptive responses of rats in the formalin test, a model of persistent pain. It was found that micro-injection of the non-selective dopamine antagonist haloperidol into the dorsolateral striatum increases formalin-induced nociception whereas injection of the non-selective dopamine agonist apomorphine reduces formalin-induced nociception. Injection of the D₁ antagonist SCH23390 or the D₁ agonist SKF38393 does not affect formalin-induced nociception. In contrast, injection of the D₂ antagonist eticlopride enhances formalin-induced nociception, whereas injection of the D₂ agonist quinpirole reduces formalin-induced nociception. These results provide additional evidence that dopamine receptors in the striatum are involved in nociception. Furthermore, this study strongly suggests that D₂, but not D₁, dopamine receptors in the dorsolateral striatum are involved in modulation of persistent nociception.     

男性同性恋者垂体性腺激素的研究

目的　研究男性同性恋者血清中垂体性腺激素水平。方法　采用放射免疫测定法对被动型同性恋组６０ 名、主动型同性恋组３２ 名和正常异性恋男性和女性对照组各３０ 名的血清中垂体性腺激素进行测定和比较。结果　被动型同性恋组血清雄激素水平［（５７２ ±１９６）μｇ／ Ｌ］ 低于主动型同性恋组［（７５２ ±３５２）μｇ／ Ｌ］ 和男性对照组［（８６５ ±３１０）μｇ／ Ｌ］ ;其雄激素与雌激素的比值（１８８ ±８６）亦低于主动型同性恋组（２４１ ±１２５） 和男性对照组（２６７ ±１４３） ;性行为对男性同性恋者的性激素水平无明显影响。结论　男性被动型同性恋者的性激素水平与主动型同性恋者和男性异性恋者存在较明显的差别。     

Activation of spinal serotonin(2A/2C) receptors augments nociceptive responses in the rat

The role of spinal 5-HT_2A/2C receptors in the regulation of spinal nociceptive transmission was studied. The 5-HT_2A/2C agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the antagonist ketanserin tartrate were administered intrathecally immediately before the formalin test. Activation of spinal 5-HT_2A/2C receptors increased the pain-like behavioural response in both the early and late phases. The findings support the hypothesis that spinal 5-HT_2A/2C receptors augment the spinal afferent nociceptive impulses induced by peripheral inflammation.     

A lack of dimorphism of sex or sexual orientation in the human anterior commissure

Four studies have examined the cross-sectional area of the anterior commissure (AC) for variation with sex, with conflicting results. One also reported the AC to be larger in homosexual as opposed to heterosexual men. We examined the cross-sectional area of the AC in postmortem material from 120 individuals, and found no variation in the size of the AC with age, HIV status, sex, or sexual orientation.     

Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat

It has been demonstrated that spinal microglial activation is involved in formalin-induced pain and that minocycline, an inhibitor of microglial activation, attenuate behavioral hypersensitivity in neuropathic pain models. We investigated whether minocycline could have any anti-nociceptive effect on inflammatory pain, after intraperitonial administration of minocycline, 1 h before formalin (5%, 50 microl) injection into the plantar surface of rat hindpaw. Minocycline (15, 30, and 45 mg/kg) significantly decreased formalin-induced nociceptive behavior during phase II, but not during phase I. The enhancement in the number of c-Fos-positive cells in the L4-5 spinal dorsal horn (DH) and the magnitude of paw edema induced by formalin injection during phase II were significantly reduced by minocycline. Minocycline inhibited synaptic currents of substantia gelatinosa (SG) neurons in the spinal DH, whereas membrane electrical properties of dorsal root ganglion neurons were not affected by minocycline. Analysis with OX-42 antibody revealed the inhibitory effect of minocycline on microglial activation 3 days after formalin injection. These results demonstrate the anti-nociceptive effect of minocycline on formalin-induced inflammatory pain. In addition to the well-known inhibitory action of minocycline on microglial activation, the anti-edematous action in peripheral tissue, as well as the inhibition of synaptic transmission in SG neurons, is likely to be associated with the anti-nociceptive effect of minocycline.     

An animal model of nociceptive peripheral neuropathy following repeated cisplatin injections

We report the assessment of motor and sensory behaviors using an electrophysiologic and an histologic approach, in a rat model of cisplatin peripheral neuropathy. Cisplatin was injected intraperitoneally one (3 mg/ kg), two (2 mg/kg), or three (1 mg/kg) times a week up to a cumulative dose of 15 or 20 mg/kg. With regard to nociceptive signs, we observed mechanical and thermal (cold stimuli) hyperalgesia and allodynia associated with minor motor disorders for the 3 mg/kg dose. Peripheral nerve conduction velocities were decreased in the cisplatin-(3 mg/kg) treated group. In addition, the histologic approach revealed that large axons were more frequently affected than the small ones, and nonmyelinated axons were unaffected. However, even in the most severe cases, myelin sheaths remained within normal limits. This animal model of nociceptive neuropathy would be suitable to study the pathophysiologic mechanisms of neuropathic pain and to test potential neuroprotective agents.