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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR004778-12
Application #
8318610
Study Section
Nursing Science: Adults and Older Adults Study Section (NSAA)
Program Officer
Marden, Susan F
Project Start
1999-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$330,655
Indirect Cost
$116,639
Name
University of Michigan Ann Arbor
Department
None
Type
Schools of Nursing
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
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
Jeong, Y; Holden, J E (2009) The role of spinal orexin-1 receptors in posterior hypothalamic modulation of neuropathic pain. Neuroscience 159:1414-21
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; Jeong, Younhee (2009) An NK1 receptor antagonist microinjected into the periaqueductal gray blocks lateral hypothalamic-induced antinociception in rats. Neurosci Lett 453:115-9
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
Holden, Janean E; Jeong, Younhee; Forrest, Jeannine M (2005) The endogenous opioid system and clinical pain management. AACN Clin Issues 16:291-301
Holden, J E; Farah, E Naleway; Jeong, Y (2005) Stimulation of the lateral hypothalamus produces antinociception mediated by 5-HT1A, 5-HT1B and 5-HT3 receptors in the rat spinal cord dorsal horn. Neuroscience 135:1255-68
Holden, Janean E; Pizzi, Julie A (2003) The challenge of chronic pain. Adv Drug Deliv Rev 55:935-48
Holden, Janean E; Van Poppel, Angela Y; Thomas, Sarah (2002) Antinociception from lateral hypothalamic stimulation may be mediated by NK(1) receptors in the A7 catecholamine cell group in rat. Brain Res 953:195-204

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