Little is known about how forebrain structures modify pain in the spinal cord dorsal horn, and whether such modulation is influenced by conditions such as sex of the subject, or the type of pain (nociceptive versus neuropathic). Using female rats, we have shown that stimulating the lateral hypothalamus (LH) in a thermal nociception model produces opposing modulation in the spinal cord dorsal horn, whereby alpha2- adrenoceptors mediate antinociception, while alpha1-adrenoceptors mediate opposing, concurrent pronociception. Antinociception predominates, but is attenuated by the pronociceptive effect. Our pilot data show that LH stimulation also produces antinociception in male rats in the thermal nociceptive model (n = 6) and in both males (n = 6) and females (n = 11) in a model of neuropathic pain (the chronic constriction injury model, or CCI). Therefore, the aim of this competing continuation proposal is to extend our findings to the CCI model and to examine sex differences in both the thermal nociception and CCI models via LH stimulation of the alpha-adrenoceptor-mediated opposing response in the spinal cord dorsal horn. In two experiments, the LH will be stimulated with carbachol in different doses (125, 250, and 500 nmol plus 62 nmol control) alone and with intrathecal injection (IT) of alpha-adrenoceptor antagonists. We will then examine the effect of sex and pain model on the mechanisms of the alpha-mediated opposing response as measured by the tail flick (TFL) and foot withdrawal latency (FWL). In all experiments, we will take blood samples to measure serum estrogen and progesterone to establish the hormonal milieu of females at the time of the experiment. Using multivariate statistical analysis, we will determine whether LH stimulation at three different carbachol doses produces different responses in alpha-adrenoceptor subtype-mediated nociceptive modulation in the thermal nociceptive and CCI models, and whether female responses differ from males. The benefits of this study come from understanding the neural mechanisms involved in endogenous analgesia that can lead to the development of more effective clinical treatments that reduce pain and promote analgesia for females as well as males. PUBLIC HEALT

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The proposed study will examine how one brain structure (lateral hypothalamus) prevents recognition of two forms of pain in male and female rats. The two forms of pain are acute pain caused by tissue injury and neuropathic pain from damage to nerves. We hypothesize that the lateral hypothalamus will decrease the recognition of both types of pain in female rats more than male rats.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
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Nursing Science: Adults and Older Adults Study Section (NSAA)
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Marden, Susan F
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University of Michigan Ann Arbor
Schools of Nursing
Ann Arbor
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Holden, Janean E; Wagner, Monica A; Reeves, Brady L (2018) Anatomical evidence for lateral hypothalamic innervation of the pontine A7 catecholamine cell group in rat. Neurosci Lett 668:80-85
Wardach, Jacob; Wagner, Monica; Jeong, Younhee et al. (2016) Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain. West J Nurs Res 38:292-307
Wagner, M; Banerjee, T; Jeong, Y et al. (2016) Sex differences in hypothalamic-mediated tonic norepinephrine release for thermal hyperalgesia in rats. Neuroscience 324:420-9
Holden, J E; Wang, E; Moes, J R et al. (2014) Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation. Neuroscience 270:226-35
Moes, Jesse R; Holden, Janean E (2014) Characterizing activity and muscle atrophy changes in rats with neuropathic pain: a pilot study. Biol Res Nurs 16:16-22
Jeong, Y; Moes, J R; Wagner, M et al. (2012) The posterior hypothalamus exerts opposing effects on nociception via the A7 catecholamine cell group in rats. Neuroscience 227:144-53
Jeong, Y; Holden, J E (2009) The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain. Neuroscience 159:1414-21
Holden, Janean E; Pizzi, Julie A; Jeong, Younhee (2009) An NK1 receptor antagonist microinjected into the periaqueductal gray blocks lateral hypothalamic-induced antinociception in rats. Neurosci Lett 453:115-9
Jeong, Younhee; Holden, Janean E (2009) Lateral hypothalamic-induced alpha-adrenoceptor modulation occurs in a model of inflammatory pain in rats. Biol Res Nurs 10:331-9
Holden, Janean E; Pizzi, Julie A (2008) Lateral hypothalamic-induced antinociception may be mediated by a substance P connection with the rostral ventromedial medulla. Brain Res 1214:40-9

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