The journal of pain : official journal of the American Pain Society
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The hippocampus is believed to play an important role in sex-based differences of pain perception. Whether estrogen potentiates allodynia in the inflamed temporomandibular joint (TMJ) through affecting the expressions of pain-related genes in the hippocampus remains largely unknown. Because the nerve growth factor (NGF) is an important gene related to inflammatory pain, we tested whether hippocampal NGF may be involved in TMJ inflammatory pain. Here we showed that the rat hippocampal NGF was upregulated by TMJ inflammation induced by complete Freund adjuvant. NGF upregulation was further potentiated by estradiol in a dose-dependent manner. In contrast, NGF transcription in the amygdala, prefrontal cortex, and thalamus was not affected by TMJ inflammation and estradiol. An intrahippocampal injection of NGF antibody or NGF receptor inhibitor K252a (inhibitor for tropomyosin receptor kinase A, TrkA) reduced the allodynia of inflamed TMJ in proestrous rats. Our data suggest that the hippocampal NGF is involved in estradiol-sensitized allodynia of inflammatory TMJ pain. ⋯ We report that complete Freund adjuvant-induced temporomandibular joint (TMJ) inflammation upregulated hippocampal nerve growth factor (NGF) expression, and estradiol replacement potentiated this upregulation. These results propose that estradiol could modulate TMJ pain through the NGF signaling pathway in the hippocampus to exacerbate TMJ pain and offer a possible mechanism of sexual dimorphism of temporomandibular disorder pain.
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Patients with chronic pain experience spontaneous or ongoing pain as well as enhanced sensitivity to evoked stimuli. Spontaneous or ongoing pain is rarely evaluated in preclinical studies. In fact, it remains controversial whether ongoing or spontaneous pain even develops in mice after tissue or nerve injury. This study tested a hypothesis that negative reinforcement can be used to unmask the presence of pain in mice with tissue or nerve injury. We found that spinal administration of clonidine or lidocaine did not elicit conditioned place preference (CPP) in uninjured or sham-operated mice. However, these agents produced CPP in mice with chronic inflammation induced by complete Freund's adjuvant (CFA) or following L5/L6 spinal nerve ligation (SNL). These data indicate the presence of non-evoked (ie, stimulus-independent) ongoing pain in mice with chronic inflammation (CFA) or following nerve injury (SNL). In addition, this study validates the use of negative reinforcement to unmask non-evoked ongoing pain in mice. Given the existence of a large collection of transgenic and knockout mice, our data show the application of this approach to elucidate molecular mechanisms underlying non-evoked pain and to contribute to drug discovery for pain. ⋯ We demonstrated the presence of non-evoked ongoing pain in mice with chronic inflammation or following nerve injury. The study also validates the use of negative reinforcement to unmask non-evoked pain in mice. We propose to apply this approach to identify molecular mechanisms and effective drugs for chronic pain.
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Preterm neonates exposed to painful procedures in the neonatal intensive care unit exhibit increased pain scores and alterations in oxygenation and heart rate. It is unclear whether these physiological responses increase the risk of oxidative stress. Using a prospective study design, we examined the relationship between a tissue-damaging procedure (TDP; tape removal during discontinuation of an indwelling central arterial or venous catheter) and oxidative stress in 80 preterm neonates. Oxidative stress was quantified by measuring uric acid (UA) and malondialdehyde (MDA) concentration in plasma before and after neonates (n = 38) experienced a TDP compared to those not experiencing any TDP (control group, n = 42). Pain was measured before and during the TDP using the Premature Infant Pain Profile (PIPP). We found that pain scores were higher in the TDP group compared to the control group (median scores, 11 and 5, respectively; P < .001). UA significantly decreased over time in control neonates but remained stable in TDP neonates (132.76 to 123.23 μM versus 140.50 to 138.9 μM; P = .002). MDA levels decreased over time in control neonates but increased in TDP neonates (2.07 to 1.81 μM versus 2.07 to 2.21 μM, P = .01). We found significant positive correlations between PIPP scores and MDA. Our data suggest a significant relationship between procedural pain and oxidative stress in preterm neonates. ⋯ This article presents data describing a significant relationship between physiological markers of neonatal pain and oxidative stress. The method described in this paper can potentially be used to assess the direct cellular effects of procedural pain as well the effectiveness of interventions performed to decrease pain.
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Spinal gamma-aminobutyric acid receptor type A (GABA(A)) receptor modulation with agonists and allosteric modulators evokes analgesia and antinociception. Changes in K(+)-Cl(-) cotransporter isoform 2 (KCC2) expression or function that occur after peripheral nerve injury can result in an impairment in the Cl(-) extrusion capacity of spinal dorsal horn neurons. This, in turn, alters Cl(-)-mediated hyperpolarization via GABA(A) receptor activation, contributing to allodynia or hypersensitivity associated with nerve injury or inflammation. A gap in knowledge exists concerning how this loss of spinal KCC2 activity differentially impacts the analgesic efficacy or potency of GABA(A) agonists and allosteric modulators. We utilized intrathecal drug administration in the tail flick assay to measure the analgesic effects of general GABA(A) agonists muscimol and Z-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA), the ∂-subunit-preferring agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), and allosteric modulators of the benzodiazepine (midazolam) and neurosteroid (ganaxolone) class, alone or in the presence of K(+)-Cl(-) cotransporter isoform (KCC) blockade. Intrathecal muscimol, ZAPA, THIP midazolam, and ganaxolone all evoked significant analgesia in the tail flick test. Coadministration of either agonists or allosteric modulators with [(dihydroindenyl)oxy] alkanoic acid (DIOA) (a drug that blocks KCC2) had no effect on agonist or allosteric modulator potency. On the other hand, the analgesic efficacy of muscimol and ZAPA and the allosteric modulator ganaxolone were markedly reduced whereas THIP and midazolam were unaffected. Finally, in the spared nerve injury model, midazolam significantly reversed tactile hypersensitivity while ganaxolone had no effect. These results indicate that the KCC2-dependent Cl(-) extrusion capacity differentially regulates the analgesic efficacy of agonists and allosteric modulators at the GABA(A) receptor complex. ⋯ Our work suggests that drug discovery efforts for the treatment of chronic pain disorders should target benzodiazepine or ∂-subunit-containing sites at the GABA(A) complex.