Anna Maria Aloisi

Sex hormones, central nervous system and pain

The aim of the present review, which highlights some relationships between sex hormones, the CNS and pain, is to provide reference points for discussion on one of the most intriguing aspects of pain pathophysiology: the presence of sex differences in the response threshold to phasic painful stimuli and in the incidence of chronic pain syndromes. The first part of the review deals with sex steroids and their mechanisms of action. In the second part, the connections between sex steroids, the CNS and pain are illustrated to introduce possible areas of discussion in the study of sex differences in experimental and clinical pain.

Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ‐opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ‐opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compounds favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.

Gonadal hormones and sex differences in pain reactivity.

BackgroundSex differences in the response threshold to painful stimuli and the higher number of chronic pain syndromes in women than in men have prompted a series of studies on lower animals and humans aimed at clarifying the role of gonadal hormones in pain. ObjectiveThis article examines the morphologic and functional aspects of gonadal hormone systems and the relations between gonadal hormones and pain circuits, to identify areas deserving of increased attention in elucidating the endocrine mechanisms that contribute to abnormal pain states.

Cognitive function in young and adult IL (interleukin)-6 deficient mice

Interleukin-6 (IL-6) is a cytokine shown to affect brain function and to be involved in pathological neurodegenerative disorders such as Alzheimers disease (AD). In the present study we investigated the cognitive function in transgenic mice not expressing IL-6 (IL-6 KO) and in wild type (WT) genotype at 4 and 12 months of age, using a passive avoidance and an eight-arm radial maze tasks. Motor function was quantified using an Animex apparatus. Hippocampal choline acetyltransferase (ChAT) activity was evaluated in both genotypes. No difference was observed in both genotypes for spontaneous motor activity. The mean latency (s) to re-enter the shock box, was similar in both young mutant and WT mice. However, a decreased sensitivity (50%) to scopolamine (1 mg/kg) in mutant compared to WT mice, was obtained. IL-6 KO mice exhibited a facilitation of radial maze learning over 30 days, in terms of a lower number of working memory errors and a higher percentage of animals reaching the criterion as compared with WT genotype tested at both ages. Furthermore, mutant mice, at the age of 12 months, showed a faster acquisition (22 days versus 30 days to reach the criterion). The pattern of arm entry exhibited by IL-6 KO mice showed a robust tendency to enter an adjacent arm at both ages, while WT only at the age of 4 months. ChAT activity was inversely correlated with memory performance. These findings suggest a possible involvement of IL-6 on memory processes, even if the mechanism remains still unclear.

Sex differences in the behavioural response to persistent pain in rats

The behavioural response to formalin-induced persistent pain was examined in male and female rats both unfamiliar and familiar with the test apparatus. Rats were subcutaneously injected with 50 microliters of formalin (10%) in the hindpaw and placed in the test cage (60 min). Licking and Flexing duration and Paw-Jerk frequency were recorded. Licking and Flexing lasted longer in females than males, while Paw-Jerk occurred in both sexes with comparable frequencies. Flexing and Paw-Jerk were lower in animals unfamiliar with the test apparatus. Therefore, behavioural responses to pain appeared to be affected by sex and familiarization with the experimental setting in different and independent ways.

Sex-dependent effects of restraint on nociception and pituitary-adrenal hormones in the rat.

The sex-dependent effects of acute restraint (RT) on nociceptive and pituitary-adrenal responses were investigated in the rat. In a first experiment, the effect of 30 min RT on pain sensitivity was evaluated through repeated use of the tail withdrawal test during and after treatment. RT induced an increase in the nociceptive threshold, i.e., analgesia, in males and females, but the duration and time-course of this effect varied between sexes. The latencies returned to approximately control values in females in the second half of RT, but in males they remained higher for the whole period of RT and immediately afterwards. Twenty-four hours later, males displayed longer latencies than controls in response to simple reexposure to the environment. In a second experiment, ACTH and corticosterone plasma levels were measured immediately after 15 or 30 min of RT. ACTH and corticosterone were higher in restrained animals than in controls after both periods of treatment, and in both sexes; however, females showed higher basal and stress corticosterone levels than males. The role played by corticosteroids in the nociceptive responses of the two sexes is discussed.

‘Mirror pain’ in the formalin test: behavioral and 2-deoxyglucose studies

&NA; Subcutaneous injection of a dilute formaldehyde solution (5 or 10%) into a hind paw induced, in the majority of rats, the appearance of ‘mirror pain’: licking the contralateral untreated hind paw 10–60 min after injection. Contralateral licking activity was much less frequent than the ipsilaterally directed one, but the overall intensities of the two responses were positively correlated. Qualitatively, the two behaviours were similar. Functional activity levels of the lumbar spinal cord, as revealed by the 2‐deoxyglucose (2‐DG) technique, were increased bilaterally over the first hour after unilateral hind limb formalin injection in unanesthetized, freely moving rats. The enhancement of the [14C]2‐DG uptake could be detected both in dorsal and ventral horns, as well as in the gray matter surrounding the central canal, and the anterolateral and dorsolateral funiculi. These metabolic changes may reflect an enhancement of the functional activity of both interneuronal pools and units projecting to supraspinal centers, giving rise to a referred contralateral pain.

Exposure to the estrogenic pollutant bisphenol A affects pain behavior induced by subcutaneous formalin injection in male and female rats.

We investigated the effects of perinatally administered bisphenol A (BPA), an environmental contaminant with estrogenic activity, on formalin-induced nociceptive responses. Male and female offspring of mother rats treated with BPA or oil were cross-fostered after birth to obtain three homogeneous groups: BPA-prenatal, receiving BPA via the placenta; BPA-postnatal, receiving BPA through suckling; OIL, control, from mothers receiving only peanut oil (vehicle). All groups underwent a pain test with s.c. formalin injection (50 microl, 10%) or were sham injected (pricking with a syringe needle) in the dorsal hind paw. They were immediately placed in an open field apparatus where pain responses (licking, flexing and paw-jerk) were recorded for 60 min. Corticosterone, testosterone and estradiol serum levels were determined in blood obtained at the end of the experiment. BPA-prenatal treatment induced an increase in licking duration in females and in flexing duration in both sexes in the first half of the test (0-30 min after formalin injection). BPA-postnatal treatment induced a decrease in paw-jerk frequency in males and females during the second part of the test (30-60 min after formalin injection). Plasma concentrations of corticosterone, estradiol and testosterone did not differ significantly between groups. These results indicate that exposure to BPA modified the activity of neural pathways and/or centers involved in nociception and pain in a sex-related and exposure-related manner.

Endocrine consequences of opioid therapy

Gonadal hormones are known to be affected by morphine and other opioids. In this paper, we summarize data collected in recent years which clearly indicate that the opioid-induced effects on steroid hormones depend on the opioid used and in some cases on the sex of the subject. Indeed morphine is able to reduce hormones like testosterone and cortisol in both male and female subjects in just a few hours, probably acting directly on peripheral glands. These depressant effects of morphine on hormones are also present in the treatment of surgical pain and are quickly reversible once opioid administration is suspended. Similar actions were also found to occur in experimental animals and in vitro in glial cells, further confirming the morphine-induced reduction of testosterone cell content. Testosterone and its metabolites are well known substances involved in the development and maintenance of the brain and all body structures. Thus when treating pain with opioids, their effects on hypothalamo-pituitary-gonadal and hypothalamo-pituitary-adrenal-related hormones must be considered and, where possible, hormone replacement therapy should be started.

Cross-sex hormone administration changes pain in transsexual women and men.

Abstract Chronic pain is gender‐related, since there is a clear predominance of one sex with respect to the other in most pain syndromes. Gonadal hormones are known to affect the occurrence and incidence of pain. Transsexuals receive cross‐sex hormones to develop and maintain somatic characteristics of the opposite sex: male to female transsexuals (MtF) are administered estrogens and anti‐androgens, while female to male transsexuals (FtM) are administered androgens. Hence, these subjects represent a model to study the relationship between sex hormones and pain. Questionnaires dealing with sociodemographic data and pain (occurrence, frequency, duration, intensity, location and associated symptoms) were administered to both MtF and FtM transsexuals under hormone treatment for sex reassignment for at least 1 year. Forty‐seven MtF and 26 FtM completed the questionnaires. Fourteen of the 47 MtF (29.8%) reported painful conditions, which in 11 subjects were not present before the beginning of hormone treatment. Pain consisted mainly of headaches and breast and musculoskeletal pain. Five subjects suffered from more than one pain condition. Sixteen of the 26 FtM (61.5%) reported pain. In 11 subjects, the pain was present before the beginning of hormone intake, and in 6 of them it improved after testosterone administration. These data suggest that marked changes in sex hormones affect the occurrence of pain in a high percentage of humans but not in all of them. Whether these effects are due to peripheral or central actions of sex steroids is unknown.