Articles: hyperalgesia.
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Although nonsteroidal anti-inflammatory drugs are the first line of therapeutics for the treatment of mild to moderate somatic pain, they are not generally considered to be effective for neuropathic pain. In the current study, direct activation of spinal Toll-like 4 receptors (TLR4) by the intrathecal (IT) administration of KDO2 lipid A (KLA), the active component of lipopolysaccharide, elicits a robust tactile allodynia that is unresponsive to cyclooxygenase inhibition, despite elevated expression of cyclooxygenase metabolites in the spinal cord. Intrathecal KLA increases 12-lipoxygenase-mediated hepoxilin production in the lumbar spinal cord, concurrent with expression of the tactile allodynia. ⋯ Similarly, pretreatment with the selective inhibitors ML127 or ML351 both reduced activity of the rat homolog of 15-LOX-1 heterologously expressed in HEK-293T cells and completely abrogated nonsteroidal anti-inflammatory drug-unresponsive allodynia in vivo after IT KLA. Finally, spinal 12/15-lipoxygenase inhibition by nordihydroguaiaretic acid (NDGA) both prevents phase II formalin flinching and reverses formalin-induced persistent tactile allodynia. Taken together, these findings suggest that spinal TLR4-mediated hyperpathic states are mediated at least in part through activation of microglial 15-LOX-1.
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Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E2 (PGE2) produced prolonged hyperalgesia (priming). ⋯ Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.
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Chemotherapeutic drugs induce various side effects including painful peripheral neuropathy that represents a major concern. The widely used anticancer drug paclitaxel causes neurological side effects such as burning pain, allodynia, and hyperalgesia. Neuroprotective substances that may effectively counteract paclitaxel-induced neuropathic symptoms are needed. ⋯ PAC-evoked neuropathic symptoms were efficiently reduced after 1 week treatment with GS dilutions 3 or 5C and the beneficial action increased after 2 weeks. GS dilutions, particularly 3C, also counteracted or prevented PAC-induced sciatic nerve axon alterations and decreased the density of intraepidermal nerve fibers. Altogether, these results obtained in the rat preclinical model suggest that GS dilution-based treatment may constitute an interesting option to explore for the long-term management of pain without undesirable effects.
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J Pain Palliat Care Pharmacother · Dec 2018
Case ReportsThe Enigma of Low-Dose Ketamine for Treatment of Opioid-Induced Hyperalgesia in the Setting of Psychosocial Suffering and Cancer-Associated Pain.
Opioid-induced hyperalgesia is a paradoxical adverse effect of opioid therapy with unclear strategies for its treatment and management. We report the successful use of low-dose ketamine infusion for the treatment of opioid-induced hyperalgesia in a 38-year-old woman presenting with psychosocial suffering and high opioid requirement secondary to pain from a poorly differentiated neuroendocrine tumor. Over the course of a month, her opioid requirement escalated to the gram level of oral morphine equivalents, upon which she was hospitalized at University of California San Diego Health for an acute on chronic pain crisis. ⋯ The infusion ultimately allowed reduction of her opioid use to a third of her original daily requirement and improved her function and ability to interact for several days. Although her pain profile became increasingly complicated by psychosocial suffering and disease progression, she did not experience the same pain event for the remainder of her hospital course. Findings from this case report demonstrate the utility of low-dose ketamine infusion in opioid-induced hyperalgesia.
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Patellofemoral pain (PFP) is a common and recurrent knee condition in young females, characterized by pressure hyperalgesia and reduced pain inhibitory control. This study investigated antinociceptive and pronociceptive profiles in young females with long-standing (>5 years) PFP (current-PFP), those who recovered from adolescent PFP (recovered-PFP), and pain-free controls. This preregistered, assessor-blinded, cross-sectional study included 87 females younger than 25 years: 36 current-PFP, 22 recovered-PFP, and 29 pain-free controls. ⋯ Compared with controls, the recovered-PFP also had reduced pressure pain thresholds at the knee, which were higher than the current-PFP (mean difference: 110-225 kPa; P < 0.05). In conclusion, both current-PFP and recovered-PFP displayed altered pain mechanisms compared to controls with no history of knee pain, despite resolution of symptoms in the recovered-PFP group. The implications of these findings in the recurrent nature of PFP requires further studies.