Chronic pain has been recognized as an underserved area of medicine. Clinical care and research are hampered by the lack of objective correlates for the subjective complaint of pain. This is especially a problem for neuropathic pain patients, where the pain is caused by malfunction of the pain-sensing neurons, rather than injury to the area where the pain is felt. ? ? In this translational project we will evaluate two types of objective evidence of neural damage to see whether they correlate with the complaint of pain. We will investigate the usefulness of these methods in adults with one of two common neuropathic pain conditions, postherpetic neuralgia (PHN) after shingles (herpes zoster), or painful neuropathy in the lower legs from diabetes mellitus, and in rat models of these conditions. Data from individuals with and without pain will be compared. We will evaluate the usefulness of tests of specific sensory functions, using standardized quantitative sensory stimuli, for predicting who does or does not have pain from shingles or diabetes. We will also evaluate the usefulness of a new technique, counting the density of pain-sensing (nociceptive) nerve endings within the epiderrnal layer of small skin punch biopsies. ? ? Surprisingly, work by our group and others show that neuropathic pain patients usually have fewer nociceptive nerve endings in painful skin. When the amount of signal coming in from the periphery decreases, pain-processing neurons in the brain and spinal cord become hyperactive. The result can be pain in the absence of tissue injury. This is similar to the development of tinnitus (ringing in the ears) when people lose hearing. Our data suggests that after shingles, PEN pain is felt by only those patients whose density of nociceptive nerve endings has been reduced below a threshold value (650 neurites/mm2 skin surface area). ? ? In Specific Aim I, we will study patients about 6 weeks after onset of shingles with quantitative sensory testing and skin biopsies, and repeat them 6 months later. We will evaluate whether data from the first set of tests, or changes between the two test sessions, can provide a marker for those who recover from pain or not.
In Specific Aim II we will compare sensory testing and skin biopsy data from normal people and diabetics with and without pain to see whether there is evidence for a threshold value separating individuals with and without pain, and whether we can identify a presymptomatic state.
In Specific Aim III, we plan to evaluate sensory function of the paw in rat models of pain after sciatic nerve injury. At sacrifice, biopsies will be taken from the bottom of the rat's paws as well as from the injured nerves to see whether changes in the density of nociceptive nerve endings in the foot correlate with severity of damage in the nerve and with the rat's behavior during sensory testing. ? ? The goal of this research is to improve medical care for patients with chronic neuropathic pain, and facilitate research by identifying """"""""biomarkers"""""""" that can be used as surrogate measures for the presence of neuropathic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Porter, Linda L
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Massachusetts General Hospital
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Oaklander, Anne Louise; Lunn, Michael Pt; Hughes, Richard Ac et al. (2017) Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev 1:CD010369
AbdelRazek, Mahmoud A; Chwalisz, Bart; Oaklander, Anne Louise et al. (2017) Evidence of small-fiber neuropathy (SFN) in two patients with unexplained genital sensory loss and sensory urinary cystopathy. J Neurol Sci 380:82-84
Oaklander, Anne Louise (2016) Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies. Neurotherapeutics 13:108-17
Oaklander, Anne Louise (2016) What is the meaning of ""small-fiber polyneuropathy"" in fibromyalgia? An alternate answer. Pain 157:1366-7
Klein, M M; Lee, J W; Siegel, S M et al. (2012) Endoneurial pathology of the needlestick-nerve-injury model of Complex Regional Pain Syndrome, including rats with and without pain behaviors. Eur J Pain 16:28-37
Unal-Cevik, Isin; Oaklander, Anne Louise (2011) Comparing partial and total tibial-nerve axotomy: long-term effects on prevalence and location of evoked pain behaviors. Pain Pract 11:109-19
Oaklander, Anne Louise (2010) Role of minimal distal nerve injury in complex regional pain syndrome-I. Pain Med 11:1251-6
Wei, Tzuping; Li, Wen-Wu; Guo, Tian-Zhi et al. (2009) Post-junctional facilitation of Substance P signaling in a tibia fracture rat model of complex regional pain syndrome type I. Pain 144:278-86
Lee, J W; Siegel, S M; Oaklander, A L (2009) Effects of distal nerve injuries on dorsal-horn neurons and glia: relationships between lesion size and mechanical hyperalgesia. Neuroscience 158:904-14
Oaklander, Anne Louise; Fields, Howard L (2009) Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol 65:629-38

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