By comparison to the primary afferent and dorsal horn neurons, our understanding of the mechanisms by which peripheral inflammatory injury leads to sustained changes in the function and properties of brainstem neurons that modulate nociception remains rudimentary. This laboratory was the first to identify that persistent inflammatory nociception enhances the antinociceptive and anti-hyperalgesic effects of MOR and DOR agon- ists in the brainstem, providing early direct evidence that persistent inflammatory nociception alters the phar- macology and physiology of bulbospinal pain modulatory neurons. Whole-cell patch-clamp recordings from RVM neurons have now identified two populations of spinally-projecting RVM neurons, one serotonergic and the other non-serotonergic, in which the postsynaptic inhibitory effect of a MOR agonist is enhanced in CFA- treated rats. These neurons also exhibit alterations in their passive membrane properties or spontaneous ac- tivity, and the strength of glutamatergic inputs to the non-serotonergic neurons is greatly increased in CFA- treated rats. We hypothesize that these neurons correspond to two populations of pain facilitatory neurons. We now propose to investigate the presynaptic mechanisms by which MOR and DOR agonists act in the RVM to produce anti-hyperalgesia. The first specific aim will use whole-cell patch clamp recording from retrogradely labeled, immunohistochemically identified RVM neurons to test three hypotheses: 1) that persistent inflamma- tory nociception increases excitatory drive to specific populations of spinally-projecting RVM neurons;2) that it enhances the ability of MOR, and possibly DOR, agonists to inhibit excitatory drive to these neurons;and 3) that the mechanism of opioid enhancement entails an upregulation of MOR, but not DOR, on glutamatergic afferents to these neurons. The second specific aim will also use whole-cell patch clamp recording to test three complementary hypotheses: 1) that persistent inflammatory nociception differentially alters inhibitory drive to specific populations of spinally-projecting RVM neurons, 2) that it increases the ability of MOR and DOR agon- ists to inhibit inhibitory drive to these same neurons;and 3) that the mechanism of enhancement entails a dif- ferential upregulation of MOR and DOR on GABAergic terminals to these neurons. Immunohistochemistry will be used to quantitate colocalization of MOR or DOR immunoreactivity with vGLUT, a marker of glutamatergic terminals, or with vGAT, a marker of GABAergic terminals, in the RVM of saline- and CFA-treated rats to ob- tain complementary anatomical data to support or refute these hypotheses. The outcome of these experiments will be a mechanistic framework for the antinociceptive and anti-hyperalgesic effects of opioids in the RVM. In turn, through studies of this class of analgesic we will be better able to identify the function of the different types of RVM neurons that are critically involved in the nociception. These data will advance our understanding of how peripheral inflammatory injury alters the responses and function of critical brainstem pain modulatory systems and inform a more rationale development of centrally-acting analgesics for the relief of persistent pain.
Persistent pain of an inflammatory nature, such as that associated with arthritis or soft tissue injury, exacts a significant financial, emotional and physical toll on its sufferers. The results of these studies will identify how persistent pain changes the function of brainstem pathways that are critically involved in the regulation of nociception and the production of analgesia. Insights gain from this work will guide the development of new, more effective pharmacotherapies or cognitive approaches for the relief of persistent pain.
|Jareczek, Francis J; White, Stephanie R; Hammond, Donna L (2017) Plasticity in Brainstem Mechanisms of Pain Modulation by Nicotinic Acetylcholine Receptors in the Rat. eNeuro 4:|
|Walder, Roxanne Y; Wattiez, Anne-Sophie; White, Stephanie R et al. (2014) Validation of four reference genes for quantitative mRNA expression studies in a rat model of inflammatory injury. Mol Pain 10:55|
|Zhang, Liang; Hammond, Donna L (2010) Cellular basis for opioid potentiation in the rostral ventromedial medulla of rats with persistent inflammatory nociception. Pain 149:107-16|
|Hamity, M V; White, S R; Hammond, D L (2010) Effects of neurokinin-1 receptor agonism and antagonism in the rostral ventromedial medulla of rats with acute or persistent inflammatory nociception. Neuroscience 165:902-13|
|Zhang, Liang; Hammond, Donna L (2009) Substance P enhances excitatory synaptic transmission on spinally projecting neurons in the rostral ventromedial medulla after inflammatory injury. J Neurophysiol 102:1139-51|
|Jongeling, Amy C; Johns, Malcolm E; Murphy, Anne Z et al. (2009) Persistent inflammatory pain decreases the antinociceptive effects of the mu opioid receptor agonist DAMGO in the locus coeruleus of male rats. Neuropharmacology 56:1017-26|
|Sykes, Kenneth T; White, Stephanie R; Hurley, Robert W et al. (2007) Mechanisms responsible for the enhanced antinociceptive effects of micro-opioid receptor agonists in the rostral ventromedial medulla of male rats with persistent inflammatory pain. J Pharmacol Exp Ther 322:813-21|
|Zhang, Liang; Jongeling, Amy C; Hammond, Donna L (2007) Suitability of the retrograde tracer Dil for electrophysiological studies of brainstem neurons: adverse ramifications for G-protein coupled receptor agonists. J Neurosci Methods 160:116-21|
|Zhang, Liang; Sykes, Kenneth T; Buhler, Amber V et al. (2006) Electrophysiological heterogeneity of spinally projecting serotonergic and nonserotonergic neurons in the rostral ventromedial medulla. J Neurophysiol 95:1853-63|
|Hurley, R W; Banfor, P; Hammond, D L (2003) Spinal pharmacology of antinociception produced by microinjection of mu or delta opioid receptor agonists in the ventromedial medulla of the rat. Neuroscience 118:789-96|
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