Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.

It is widely reported that analgesic drugs acting at mu, kappa, and delta opioid-receptors display quantitative and qualitative differences in effect in males and females. These sex-related differences are not restricted to the analgesic/antinociceptive properties of opioids, but are also present in opioid-induced side effects, such as changes in respiration, locomotor activity, learning/memory, addiction, and changes in the cardiovascular system. An increasing number of well-controlled animal and human studies directly examining the issue of sex in the potency of opioids show that, although sex may affect opioid analgesia, the direction and magnitude of sex differences depend on many interacting variables. These include those specific to the drug itself, such as dose, pharmacology, and route and time of administration, and those particular to the subject, such as species, type of pain, genetics, age, and gonadal/hormonal status. In the current review, we systematically present these animal and human studies and discuss the data in relation to the depending variables. Although the observed sex differences in opioid effect may be clinically relevant, lack of knowledge on other factors involved in the large variability in patient opioid analgesic sensitivity should compel practitioners to customize their dosing regimens based on individual requirements.

PURPOSE. Adolescents with inflammatory bowel disease (IBD) may be at heightened risk for developing anxiety and depression. This cross-sectional pilot study examined the relationship between anxiety and depression and health-related behaviors. METHODS. Thirty-six adolescents with diagnosed IBD, ages 12-17, and their parents were recruited from two pediatric gastroenterology medical centers. RESULTS. Clinical levels of anxiety (22%) and depressive symptoms (30%) were reported by patients. Regression analyses revealed that IBD-specific anxiety was significantly associated with greater utilization of medical services and worsened psychosocial functioning. PRACTICE IMPLICATIONS. Results provide preliminary support that IBD-specific anxiety may play an important role in disease management, yet concerns are rarely systematically assessed by health professionals.

Background N-Methyl-d-aspartate receptor antagonists reverse hyperalgesia during morphine infusion in male mice only. Because the melanocortin-1 receptor can act as a female-specific counterpart to N-methyl-d-aspartate receptors in κ-opioid analgesic mechanisms, the authors assessed the contribution of melanocortin-1 receptors to the sex-specific mechanisms underlying morphine hyperalgesia. Methods The tail-withdrawal test was used to compare the nociceptive responses of male and female C57BL/6J (B6) mice with those of C57BL/6J-Mc1re/e (e/e) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.6 and 40.0 mg kg−1 · 24 h−1). Separate groups of hyperalgesic B6 and outbred CD-1 mice were injected with MK-801 or MSG606, selective N-methyl-d-aspartate and melanocortin-1 receptor antagonists, respectively. Results Morphine infusion (40.0 mg · kg−1 · 24 h−1) reduced baseline withdrawal latencies by 45–55% in B6 mice of both sexes, indicating hyperalgesia; this increased nociception was manifest in male e/e mice only. Although MK-801 reversed hyperalgesia in male mice only, increasing latencies by 72%, MSG606 increased latencies by approximately 60% exclusively in females. A lower morphine infusion dose (1.6 mg · kg−1 · 24 h−1) reduced baseline withdrawal latencies by 45–52% in B6 and e/e mice of both sexes, which was reversed by MK-801, but not MSG606, in both male and female B6 mice. Conclusions The data indicate the sex-specific mediation of highdose morphine-induced hyperalgesia by N-methyl-d-aspartate and melanocortin-1 receptors in male and female mice, respectively, suggesting a broader relevance of this known sexual dimorphism. The data further indicate that the neural substrates contributing to hyperalgesia are morphine dose-dependent.

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The µ opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing in rodents and humans, with dozens of alternatively spliced variants of the OPRM1 gene. The present studies establish a SYBR green quantitative PCR (qPCR) assay to more accurately quantify mouse OPRM1 splice variant mRNAs. Using these qPCR assays, we examined the expression of OPRM1 splice variant mRNAs in selected brain regions of four inbred mouse strains displaying differences in µ opioid-induced tolerance and physical dependence: C56BL/6J, 129P3/J, SJL/J and SWR/J. The complete mRNA expression profiles of the OPRM1 splice variants reveal marked differences of the variant mRNA expression among the brain regions in each mouse strain, suggesting region-specific alternative splicing of the OPRM1 gene. The expression of many variants was also strain-specific, implying a genetic influence on OPRM1 alternative splicing. The expression levels of a number of the variant mRNAs in certain brain regions appear to correlate with strain sensitivities to morphine analgesia, tolerance and physical dependence in four mouse strains.

These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-D-aspartate receptor is also indicated.

Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7-benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; δ 1 , δ 2 , and κ opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas δ 1 , δ 2 , NMDA, and AMPA receptors enable acute and chronic heroin dependence, κ receptor activity limits the dependence liability of chronic heroin. With the exception of δ 1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of κ receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute an chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.