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Positive allosteric modulation of TRPV1 as a novel analgesic mechanism
S54
Abstracts
The Journal of Pain
(312) Sickle cell disease patients on opioids do not show hyperalgesia on QST measures of pain sensitivity P Carroll, C Campbell, K Bond, L McCauley, C Haywood, S Lanzkron, R Edwards, and J Haythornthwaite; Johns Hopkins University, Baltimore, MD
E19 Noninvasive Brain Imaging (314) Resting state BOLD signal periodicity in low-back pain patient’s hippocampus
Sickle Cell Disease (SCD) is a rare, autosomal recessive hemoglobinopathy that affects about 100,000 Americans. It causes episodic acute pain and development of a complex chronic pain syndrome is common. The mechanism of the pain is mostly unknown. Many patients are exposed to high dose opioids throughout life, often including chronic opioid therapy (COT). There is some evidence that opioids may cause paradoxical hypersensitivity to pain, which may be a particular problem for people prone to episodes of acute pain. The present study was part of an ongoing project to examine pain phenotypes in patients with SCD. One group of patients receiving COT (n=19) were compared to a group who were not (n=26) on a comprehensive battery of quantitative sensory tests which included thermal and pain pressure thresholds, mechanical temporal summation, individually tailored thermal temporal summation, and hot water diffuse noxious inhibitory control (DNIC). Participants were 37.8% male, had a mean age of 37.2 years, and were all African Americans. While generally pressure pain thresholds were somewhat lower and thermal and mechanical temporal summation were somewhat greater in the opioid group, these group effects were not statistically significant and measured effect sizes were modest. The study yielded little evidence of opioid-induced hyperalgesia in this population, though greater sample sizes might reveal small differences. Supported by NIH grant 5R01HL098110.
E Stringer, L Jastrzab, and J Younger; Stanford School of Medicine, Palo Alto, CA
(313) Buprenorphine produces antinociception independent of periaqueductal gray activation
E20 Non-Opioid Analgesics
R Haseman, M Morgan, K Suchland, and N Lautermilch; Washington State University, Vancouver, WA The antinociceptive effect of opioids are mediated in part by the nociceptive modulatory system that descends from the periaqueductal gray (PAG) to rostral ventromedial medulla to spinal cord. Microinjection into the ventrolateral PAG of any of a number of opioids (e.g., morphine, fentanyl, DAMGO) produces antinociception in the rat. Buprenophine is a unique opioid in that it is an agonist at the mu-opioid receptor and an antagonist at the kappa opioid receptor. Given that the antinociceptive effects of opioids microinjected into the PAG are mediated primarily by mu-opioid receptors, microinjection of buprenorphine into the PAG should produce potent antinociception. This hypothesis was tested by measuring nociception using the hot-plate test following microinjection of buprenorphine into the PAG of awake, behaving rats. Surprisingly, no antinociception was evident following microinjection of buprenorphine (1 or 100 ng/0.4 ml) into the PAG at any of the time points tested (5 – 120 min). In contrast, subcutaneous administration of buprenorphine (100 mg) produced clear antinociception from 15 to at least 120 min following the injection. In order to determine whether buprenorphine acts as a mu-opioid receptor antagonist in the PAG, buprenorphine (100 ng) was microinjected into the PAG 15 min prior to microinjection of the mu-opioid receptor agonist DAMGO (0.24 – 0.54 mg). Buprenorphine had no effect on the antinociceptive effect produced by microinjecting DAMGO into the PAG. These data indicate that the PAG contributes to the antinociceptive effects of some, but not all opioids, and that the antinociception produced by buprenorphine does not involve the PAG. These findings are consistent with a growing literature showing ligand specific signaling at the mu-opioid receptor. Support provided by Purdue Pharma L.P.
We report here the case of a low-back pain individual who shows rhythmic fluctuations in hippocampal neural activity. Resting state functional magnetic resonance imaging (fMRI) studies record signal over time without extrinsic stimuli and may be used to assess functional connectivity between regions. Functional connectivity can be evaluated by measuring the correlations in spontaneous fluctuations of blood oxygen level dependent (BOLD) signals from different regions across the brain, providing a systems level evaluation of the integration of individual regions within an intrinsic neural network. This case was detected in a study examining opioid treatment effects on the human brain. During our analysis, we discovered that one participant possessed hippocampal BOLD signal fluctuations with exact periodicity, 0.023Hz, pre-treatment and post-treatment. The resting state BOLD signal pattern is strikingly similar to on/off task design BOLD signal time courses, here mimicking 22s on and 22s off. This frequency fluctuation in the BOLD signal persisted beyond the resting state scan and could be seen in both heat-pain and cold-pain task scans, where the tasks paradigms (20s on and 30s off, and 20s on and 32s off, respectively) were not synced with the BOLD signal fluctuations. Additionally, the BOLD signal fluctuations did not correlate with head motion, heart rate, or respiratory rate. Due to the oddity in the BOLD signal observed in the participant’s hippocampus, we asked the participant to return for a third scan, over a year after the first scan. We repeated the same resting state functional scan protocol. The 0.023-Hz BOLD signal periodicity within the hippocampus was still observable. This is the first report we know of where someone exhibits such periodicity in the BOLD signal fluctuations in the resting state.
(315) Positive allosteric modulation of TRPV1 as a novel analgesic mechanism E Lebovitz, K Kaszas, J Keller, and M Iadarola; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD The chronic pain epidemic has risen to affect approximately 116 million adults in America resulting in a nearly 4-fold increase in opiate prescriptions over the last decade, which has contributed to greater narcotic abuse and fatalities. To circumvent opioid-based analgesic mechanisms, we are exploring novel pharmacological approaches using the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly myelinated A-delta fibers that detect low and high rates of noxious heating, respectively, and is also activated by vanilloids (capsaicin, resiniferatoxin) and low pH. Vanilloid agonist binding can inactivate primary afferents, therefore we hypothesize that positive allosteric modulation of TRPV1 will produce a selective, temporary blockade of nociceptive nerve terminals that innervate sites of inflammation or tissue damage. As such, we have identified several compounds which potentiate vanilloid and pH activation of TRPV1 in vitro including MRS1477. To study its effect in vivo, we injected the left hindpaw of male adult rats with 30 mg capsaicin +/- MRS1477 in a blinded fashion. An infrared laser was then used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses at 24 and 48 hours post-injection were recorded. At the times tested for thermal sensitivity, withdrawal responses of the capsaicin treated paw were not significantly different from the untreated contralateral paw. However, rats treated with capsaicin and MRS1477 showed decreased response intensity and increased withdrawal latency compared to control, indicative of channel potentiation, nerve terminal inactivation, and analgesia. Future studies will examine TRPV1 modulation by MRS1477 in inflammatory models to determine if orthosteric endovanilloids can substitute for capsaicin in vivo. The present observations suggest a new non-narcotic, selective, long lasting TRPV1-based approach to pain reduction that may be effective in acute, persistent, or chronic pain disorders.
Abstracts
The Journal of Pain
(312) Sickle cell disease patients on opioids do not show hyperalgesia on QST measures of pain sensitivity P Carroll, C Campbell, K Bond, L McCauley, C Haywood, S Lanzkron, R Edwards, and J Haythornthwaite; Johns Hopkins University, Baltimore, MD
E19 Noninvasive Brain Imaging (314) Resting state BOLD signal periodicity in low-back pain patient’s hippocampus
Sickle Cell Disease (SCD) is a rare, autosomal recessive hemoglobinopathy that affects about 100,000 Americans. It causes episodic acute pain and development of a complex chronic pain syndrome is common. The mechanism of the pain is mostly unknown. Many patients are exposed to high dose opioids throughout life, often including chronic opioid therapy (COT). There is some evidence that opioids may cause paradoxical hypersensitivity to pain, which may be a particular problem for people prone to episodes of acute pain. The present study was part of an ongoing project to examine pain phenotypes in patients with SCD. One group of patients receiving COT (n=19) were compared to a group who were not (n=26) on a comprehensive battery of quantitative sensory tests which included thermal and pain pressure thresholds, mechanical temporal summation, individually tailored thermal temporal summation, and hot water diffuse noxious inhibitory control (DNIC). Participants were 37.8% male, had a mean age of 37.2 years, and were all African Americans. While generally pressure pain thresholds were somewhat lower and thermal and mechanical temporal summation were somewhat greater in the opioid group, these group effects were not statistically significant and measured effect sizes were modest. The study yielded little evidence of opioid-induced hyperalgesia in this population, though greater sample sizes might reveal small differences. Supported by NIH grant 5R01HL098110.
E Stringer, L Jastrzab, and J Younger; Stanford School of Medicine, Palo Alto, CA
(313) Buprenorphine produces antinociception independent of periaqueductal gray activation
E20 Non-Opioid Analgesics
R Haseman, M Morgan, K Suchland, and N Lautermilch; Washington State University, Vancouver, WA The antinociceptive effect of opioids are mediated in part by the nociceptive modulatory system that descends from the periaqueductal gray (PAG) to rostral ventromedial medulla to spinal cord. Microinjection into the ventrolateral PAG of any of a number of opioids (e.g., morphine, fentanyl, DAMGO) produces antinociception in the rat. Buprenophine is a unique opioid in that it is an agonist at the mu-opioid receptor and an antagonist at the kappa opioid receptor. Given that the antinociceptive effects of opioids microinjected into the PAG are mediated primarily by mu-opioid receptors, microinjection of buprenorphine into the PAG should produce potent antinociception. This hypothesis was tested by measuring nociception using the hot-plate test following microinjection of buprenorphine into the PAG of awake, behaving rats. Surprisingly, no antinociception was evident following microinjection of buprenorphine (1 or 100 ng/0.4 ml) into the PAG at any of the time points tested (5 – 120 min). In contrast, subcutaneous administration of buprenorphine (100 mg) produced clear antinociception from 15 to at least 120 min following the injection. In order to determine whether buprenorphine acts as a mu-opioid receptor antagonist in the PAG, buprenorphine (100 ng) was microinjected into the PAG 15 min prior to microinjection of the mu-opioid receptor agonist DAMGO (0.24 – 0.54 mg). Buprenorphine had no effect on the antinociceptive effect produced by microinjecting DAMGO into the PAG. These data indicate that the PAG contributes to the antinociceptive effects of some, but not all opioids, and that the antinociception produced by buprenorphine does not involve the PAG. These findings are consistent with a growing literature showing ligand specific signaling at the mu-opioid receptor. Support provided by Purdue Pharma L.P.
We report here the case of a low-back pain individual who shows rhythmic fluctuations in hippocampal neural activity. Resting state functional magnetic resonance imaging (fMRI) studies record signal over time without extrinsic stimuli and may be used to assess functional connectivity between regions. Functional connectivity can be evaluated by measuring the correlations in spontaneous fluctuations of blood oxygen level dependent (BOLD) signals from different regions across the brain, providing a systems level evaluation of the integration of individual regions within an intrinsic neural network. This case was detected in a study examining opioid treatment effects on the human brain. During our analysis, we discovered that one participant possessed hippocampal BOLD signal fluctuations with exact periodicity, 0.023Hz, pre-treatment and post-treatment. The resting state BOLD signal pattern is strikingly similar to on/off task design BOLD signal time courses, here mimicking 22s on and 22s off. This frequency fluctuation in the BOLD signal persisted beyond the resting state scan and could be seen in both heat-pain and cold-pain task scans, where the tasks paradigms (20s on and 30s off, and 20s on and 32s off, respectively) were not synced with the BOLD signal fluctuations. Additionally, the BOLD signal fluctuations did not correlate with head motion, heart rate, or respiratory rate. Due to the oddity in the BOLD signal observed in the participant’s hippocampus, we asked the participant to return for a third scan, over a year after the first scan. We repeated the same resting state functional scan protocol. The 0.023-Hz BOLD signal periodicity within the hippocampus was still observable. This is the first report we know of where someone exhibits such periodicity in the BOLD signal fluctuations in the resting state.
(315) Positive allosteric modulation of TRPV1 as a novel analgesic mechanism E Lebovitz, K Kaszas, J Keller, and M Iadarola; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD The chronic pain epidemic has risen to affect approximately 116 million adults in America resulting in a nearly 4-fold increase in opiate prescriptions over the last decade, which has contributed to greater narcotic abuse and fatalities. To circumvent opioid-based analgesic mechanisms, we are exploring novel pharmacological approaches using the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly myelinated A-delta fibers that detect low and high rates of noxious heating, respectively, and is also activated by vanilloids (capsaicin, resiniferatoxin) and low pH. Vanilloid agonist binding can inactivate primary afferents, therefore we hypothesize that positive allosteric modulation of TRPV1 will produce a selective, temporary blockade of nociceptive nerve terminals that innervate sites of inflammation or tissue damage. As such, we have identified several compounds which potentiate vanilloid and pH activation of TRPV1 in vitro including MRS1477. To study its effect in vivo, we injected the left hindpaw of male adult rats with 30 mg capsaicin +/- MRS1477 in a blinded fashion. An infrared laser was then used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses at 24 and 48 hours post-injection were recorded. At the times tested for thermal sensitivity, withdrawal responses of the capsaicin treated paw were not significantly different from the untreated contralateral paw. However, rats treated with capsaicin and MRS1477 showed decreased response intensity and increased withdrawal latency compared to control, indicative of channel potentiation, nerve terminal inactivation, and analgesia. Future studies will examine TRPV1 modulation by MRS1477 in inflammatory models to determine if orthosteric endovanilloids can substitute for capsaicin in vivo. The present observations suggest a new non-narcotic, selective, long lasting TRPV1-based approach to pain reduction that may be effective in acute, persistent, or chronic pain disorders.