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To characterize the impacts of policies intended to improve opioid prescribing and prevent opioid-related overdose and death on individuals who take opioids.
Learn More >Central sensitization is a condition in which there is an abnormal responsiveness to nociceptive stimuli. As such, the process may contribute to the development and maintenance of pain. Factors influencing the propensity for development of central sensitization have been a subject of intense debate and remain elusive. Injury-induced secondary hyperalgesia can be elicited by experimental pain models in humans, and is believed to be a result of central sensitization. Secondary hyperalgesia may thus reflect the individual level of central sensitization. The objective of this study was to investigate possible associations between increasing size of secondary hyperalgesia area and brain connectivity in known resting-state networks. We recruited 121 healthy participants (male, age 22, SD 3.35) who underwent resting-state functional magnetic resonance imaging. Prior to the scan session, areas of secondary hyperalgesia following brief thermal sensitization (3 min. 45 °C heat stimulation) were evaluated in all participants. 115 participants were included in the final analysis. We found a positive correlation (increasing connectivity) with increasing area of secondary hyperalgesia in the sensorimotor- and default mode networks. We also observed a negative correlation (decreasing connectivity) with increasing secondary hyperalgesia area in the sensorimotor-, fronto-parietal-, and default mode networks. Our findings indicate that increasing area of secondary hyperalgesia is associated with increasing and decreasing connectivity in multiple networks, suggesting that differences in the propensity for central sensitization, assessed as secondary hyperalgesia areas, may be expressed as differences in the resting-state central neuronal activity.
Learn More >Intrathecal drug delivery has been well established an effective and safe method for the treatment of pain, including palliative cancer-related and chronic nonmalignant pain. In this article, we discuss the role of intrathecal pain therapy in the management of chronic, refractory nonmalignant pain. Common indications, patient selection criteria, medication options, complications, and adverse events are discussed within the context of results from randomized controlled trials, clinical consensus guidelines, and best available literature to date.
Learn More >Prior studies have found a substantial risk of persistent opioid use among adolescents and young adults undergoing surgical and dental procedures. It is unknown whether family-level factors, such as long-term opioid use in family members, is associated with persistent opioid use.
Learn More >Activation of cannabinoid CB receptors suppresses pathological pain but also produces unwanted side effects, including tolerance and physical dependence. Inhibition of fatty-acid amide hydrolase (FAAH), the major enzyme catalyzing the degradation of anandamide (AEA), an endocannabinoid, and other fatty-acid amides, suppresses pain without unwanted side effects typical of direct CB agonists. However, FAAH inhibitors have failed to show efficacy in several clinical trials suggesting that the right partnership of FAAH inhibition and pathology has yet to be identified. We compared efficacy of chronic treatments with a centrally penetrant FAAH inhibitor (URB597), a peripherally-restricted FAAH inhibitor (URB937) and an orthosteric pan-cannabinoid agonist (WIN55,212-2) in suppressing neuropathic pain induced by the chemotherapeutic agent paclitaxel. Each FAAH inhibitor suppressed the development of paclitaxel-induced neuropathic pain and reduced the maintenance of already established allodynia with sustained efficacy. Tolerance developed to the anti-allodynic efficacy of WIN55,212-2, but not to that of URB597 or URB937, in each dosing paradigm. Challenge with the CB antagonist rimonabant precipitated CB-dependent withdrawal in paclitaxel-treated mice receiving WIN55,212-2 but not URB597 or URB937. When dosing with either URB597 or URB937 was restricted to the development of neuropathy, paclitaxel-induced allodynia emerged following termination of drug delivery. These observations suggest that both FAAH inhibitors were anti-allodynic rather than curative. Moreover, neither URB597 nor URB937 impeded the ability of paclitaxel to reduce breast (4T1) or ovarian (HeyA8) tumor cell line cytotoxicity. In fact, URB597 and URB937 alone reduced 4T1 tumor cell line cytotoxicity, albeit with low potency, and the dose matrix of each combination with paclitaxel was synergistic in reducing 4T1 and HeyA8 tumor cell line viability according to Bliss, Highest Single Agent (HSA) and Loewe additivity models. Both FAAH inhibitors synergized with paclitaxel to reduce 4T1 and HeyA8 tumor cell line viability without reducing viability of non-tumor HEK293 cells. Neither FAAH inhibitor reduced viability of non-tumor HEK293 cells in either the presence or absence of paclitaxel, suggesting that nonspecific cytotoxic effects were not produced by the same treatments. Our results suggest that FAAH inhibitors reduce paclitaxel-induced allodynia without the occurrence of CB-dependence in vivo and may, in fact, enhance the anti-tumor actions of paclitaxel in vitro.
Learn More >Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.
Learn More >Tolerance to cannabinoid agonists can develop through desensitization of the cannabinoid receptor 1 (CB) following prolonged administration. Desensitization results from phosphorylation of CB by a G protein-coupled receptor kinase (GRK), and subsequent association of the receptor with arrestin. Mice expressing a mutant form of CB, in which the serine residues at two putative phosphorylation sites necessary for desensitization have been replaced by non-phosphorylatable alanines (S426A/S430A), display reduced tolerance to Δ-tetrahydrocannabinol (Δ-THC). Tolerance to the antinociceptive effects of WIN55,212-2 was delayed in S426A/S430A mutants using the tail-flick and formalin tests. However, tolerance to the antinociceptive effects of once daily CP55,940 injections was not significantly delayed in S426A/S430A mutant mice using either of these tests. Interestingly, the dose response curve shifts for the hypothermic and antinociceptive effects of CP55,940 that were induced by chronic treatment with this agonist in wild-type mice were blocked in S426A/S430A mutant mice. Assessment of mechanical allodynia in mice exhibiting chronic cisplatin-evoked neuropathic pain found that tolerance to the anti-allodynic effects WIN55,212-2 but not CP55,940 was delayed in S426A/S430A mice compared to wild-type littermates. Despite these deficits in tolerance, S426A/S430A mutant mice eventually developed tolerance to both WIN55,212-2 and CP55,940 for all pain assays that were examined, suggesting that other mechanisms likely contribute to tolerance for these cannabinoid agonists. These findings suggest that GRK- and βarrestin2-mediated desensitization of CB may strongly contribute to the rate of tolerance to the antinociceptive effects of WIN55,212-2, and raises the possibility of agonist-specific mechanisms of cannabinoid tolerance.
Learn More >To describe and analyze Twitter activity associated with American Headache Society (AHS) conferences and evaluate the potential for Twitter to promote education and public outreach.
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