The effect of repeated early injury on reward-related processing in the adult rat

Pain during early life can affect the developing central nervous system, leading to altered neural function in the adult organism. In this thesis, I investigate the long-term effects of repeated early pain on reward-related processing in the adult rat. I hypothesised that the reward system was likely to be sensitive to early activation of pain pathways, as the brain systems involved in both pain and reward overlap extensively, and virtually all centrally acting analgesic drugs are also drugs of reward. To begin, I investigate the extent to which the developing reward system is activated by a classic analgesic and drug of abuse, morphine. Comparing neonatal and adult activation of the dopaminergic system, results show that a single morphine challenge activates neonatal reward pathways, but that there are qualitative differences in the neonatal response to repeated morphine. Next, I show how reward-related behaviours of adult animals repeatedly injured as neonates differ from those of uninjured littermates, and finally propose the lateral hypothalamic orexin system as a biomarker reflecting this behaviour. The results provide evidence that neonatal injury interferes with the normal development of reward systems during a critical period of development, resulting in characteristic changes in reward behaviour and cell signalling in the adult animal

Lycium barbarum (wolfberry) polysaccharide facilitates ejaculatory behaviour in male rats

Poster Session AOBJECTIVE: Lycium barbarum (wolfberry) is a traditional Chinese medicine, which has been considered to have therapeutic effect on male infertility. However, there is a lack of studies support the claims. We thus investigated the effect of Lycium barbarum polysaccharide (LBP), a major component of wolfberry, on male rat copulatory behavior. METHOD: Sprague-Dawley rats were divided into two groups (n=8 for each group). The first group received oral feeding of LBP at dosage of 1mg/kg daily. The control group received vehicle (0.01M phosphate-buffered saline, served as control) feeding daily for 21 days. Copulatory tests were conducted at 7, 14 and 21 days after initiation of treatment. RESULTS: Compared to control animals, animals fed with 1mg/kg LBP showed improved copulatory behavior in terms of: 1. Higher copulatory efficiency (i.e. higher frequency to show intromission rather than mounting during the test), 2. higher ejaculation frequency and 3. Shorter ejaculation latency. The differences were found at all time points (Analyzed with two-tailed student’s t-test, p<0.05). There is no significant difference found between the two groups in terms of mount/intromission latency, which indicates no difference in time required for initiation of sexual activity. Additionally, no difference in mount frequency and intromission frequency was found. CONCLUSION: The present study provides scientific evidence for the traditional use of Lycium barbarum on male sexual behavior. The result provides basis for further study of wolfberry on sexual functioning and its use as an alternative treatment in reproductive medicine.postprintThe 30th Annual Meeting of the Australian Neuroscience Society, in conjunction with the 50th Anniversary Meeting of the Australian Physiological Society (ANS/AuPS 2010), Sydney, Australia, 31 January-3 February 2010. In Abstract Book of ANS/AuPS, 2010, p. 177, abstract no. POS-TUE-19

Peripheral Neuropathy

Understanding the rapid changes in the evaluation and management of peripheral neuropathies, as well as the complexity of their mechanism, is a mandatory requirement for the practitioner to optimize patient's care. The objective of this book is to update health care professionals on recent advances in the pathogenesis, diagnosis and treatment of peripheral neuropathy. This work was written by a group of clinicians and scientists with large expertise in the field

Stimulating Glial Gq-Coupled GPCR Pathways Blocks Acute Pain and Itch

Glial G protein-coupled receptor (GPCR) pathways have been linked to synaptic modulation. However, their roles in pain and itch processing are unknown and have been difficult to study because glia and neurons often express overlapping GPCRs. The transgenic mouse model glial fibrillary acidic protein-Designer Receptor Exclusively Activated by a Designer Drug (GFAP-DREADD) is a useful model for selectively stimulating Gq-GPCR pathways on GFAP-positive cells. Gq-DREADD is expressed in astrocytes, but not neurons, in the spinal cord. Imaging studies demonstrated that Gq-DREADD stimulation causes calcium increases in astrocytes in lamina II and V of the spinal cord in slices from Gq-DREADD mice but not in those from wild-type mice. Stimulating Gq-DREADD caused a long-lasting antinociceptive phenotype for Gq-DREADD mice but not for wild-type mice as measured using the Hargreaves test. Selective stimulation of spinal cord and DRG Gq-DREADD was sufficient to mediate this effect. Surprisingly, removal of the IP3R2 receptor did not affect Gq-DREADD-mediated antinociception, suggesting that stimulation of GFAP-positive Gq-GPCR pathways can inhibit pain transmission in an IP3R2-independent manner. C-fos has been used as a marker of neuronal activity in response to noxious stimuli. Gq-DREADD stimulation did not alter the ability of noxious stimuli to induce c-fos in the dorsal horn. Nociceptors make their central projections in the dorsal horn, and a decrease in excitatory neurotransmission at this synapse would be antinociceptive. We examined this hypothesis by performing dorsal root stimulation experiments and found that Gq-DREADD stimulation did not modulate evoked field potentials in lamina II. The neurocircuitry that is used in pain processing has a large degree of overlap with itch-sensitive neurocircuitry. Gq-DREADD stimulation was also shown to block histamine-dependent itch, and this phenotype appears to be peripherally mediated. Collectively, our experiments indicate that Gq-GPCR pathways in GFAP-positive glia can be antinociceptive in the setting of acute pain and can mediate antinociception in an IP3R2-independent manner. In addition, Gq-GPCR pathways in astrocytes can block acute itch. These data provide insight into the roles that glial Gq-GPCR pathways play in the modulation of acute pain and itch, which may lead to the development of novel therapies for chronic pain and itch neuropathies.Doctor of Philosoph

TARGETING METHYLGLYOXAL AND PPAR GAMMA TO ALLEVIATE NEUROPATHIC PAIN ASSOCIATED WITH TYPE 2 DIABETES

Neuropathic pain affects up to 50% of the 29 million diabetic patients in the United States. Neuropathic pain in diabetes manifests as a disease of the peripheral and central nervous systems. The prevalence of type 2 diabetes is far greater than type 1 (90%), yet the overwhelming focus on type 1 models this has left the mechanisms of pain in type 2 diabetes largely unknown. Therefore I aimed to improve the current mechanistic understanding of pain associated with type 2 diabetes using two preclinical rodent models: Zucker Diabetic Fatty rats and db/db mice. In addition, I highlight the translational importance of simultaneous measurement of evoked/sensory and non-evoked/affective pain-related behaviors in preclinical models. This work is the first to show a measure of motivational-affective pain in a model of type 2 diabetes. I used methodological approaches including: (1) immunohistochemical and calcium imaging to assess stimulus-evoked sensitization; (2) measurement nociceptive behaviors and evoked sensory thresholds as well as pain affect using novel mechanical conflict avoidance and conditioned place preference/aversion assays; (3) pharmacological and genetic manipulation of methylglyoxal, TRPA1, AC1, and PPARγ. I hypothesized that the thiazolidinedione class of peroxisome proliferator-activated receptor gamma (PPARγ) agonists would reduce neuropathic pain-like behavior and spinal neuron sensitization in traumatic nerve injury and type 2 diabetes. As PPARγ is a nuclear receptor, and already targeted clinically to promote cellular insulin sensitization to reduce hyperglycemia, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. In two separate research aims, I challenged this view and tested whether the PPARγ agonist pioglitazone would (1) rapidly alleviate neuropathic pain through a non-genomic mechanism and (2) reduce painful sensitization in nociceptive and neuropathic pain models independent from lowering blood glucose. I aimed to investigate the contribution of the glucose metabolite methylglyoxal to painful type 2 diabetes. I tested the hypothesis that methylglyoxal produces nociceptive, evoked, and affective pain that is dependent on activation of the sensory neuron cation channel TRPA1 and the secondary messenger enzyme AC1. I also tested whether pioglitazone or the novel methylglyoxal scavenging peptide GERP10 could alleviate painful type 2 diabetes

Pain After Breast Cancer Surgery is Predicted by Pre-Operative Immunological and Psychological Factors

This study identified risk factors for pain intensity at rest and with movement, pain qualities and neuropathic pain 24 hours post-breast cancer surgery (BCS). Before surgery 86 women completed demographic, health status, and psychological questionnaires and blood was drawn to measure baseline cytokine levels. Numeric Rating Scale-Rest (NRS-R), NRS-Movement (NRS-M), Short-Form McGill Pain Questionnaire (SF-MPQ) and Short-Form Neuropathic Pain Questionnaire (SF-NPQ) were completed 24 hours post-BCS. Backward regression models found significant correlates for NRS-R: younger age, increased pain catastrophizing and bilateral surgery; NRS-M: younger age, increased trait anxiety, bilateral surgery, and mastectomy; SF-MPQ: increased pain catastrophizing, bilateral surgery, and previous breast surgery; and SF-NPQ: decreased interleukin-10 and increased pain catastrophizing. These results support the biopsychosocial model of pain and the importance of measuring multiple pain outcomes. Variables accounting for the most variance in each outcome (pain catastrophizing [NRS-R; SF-MPQ], trait anxiety [NRS-M] and baseline IL-10 [SF-NPQ]) are potentially modifiable