The journal of pain : official journal of the American Pain Society
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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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The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. ⋯ This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation.
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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.
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Recently, the lexicon of pain was refined into a parsimonious set of words making up the Pain Descriptor System (PDS). The present study investigated the latent structure of the sensory category of the PDS with its 24 descriptors distributed equally across 8 subcategories. A sample of 629 chronic pain patients rated the degree to which each of these words described their pain. It was found that coldness-related words were rarely used and shared high covariance with other descriptors, thus warranting their removal as a subcategory. Confirmatory factor analysis of a previously theorized single higher-order model of 7 latent factors (each with 3 observed variables) resulted in poor fit, x(2)(181) = 377.72, P < .05; comparative fit index (CFI) = .915; root mean square error of approximation (RMSEA) = .04. This model was replaced with a dual higher-order model retaining the same 7 latent factors plus 2 higher-order factors corresponding to deep pain versus superficial pain. This model provided a good representation of the data, x(2)(181) = 301.07, P < .05; CFI = .948; RMSEA = .032. Therefore, descriptors of pain sensation differentiate sensory quality while also reflecting a fundamental dichotomy supported by neurophysiological research. Thus, the lexicon can illuminate pathophysiology, thereby clarifying pain diagnoses. ⋯ Confirmatory factor analysis was performed on pain sensation descriptors used by 629 patients. This supported a hierarchical model with 7 lower-order factors plus 2 higher-order factors corresponding to deep pain versus superficial pain. By reflecting neurophysiology, this lexicon of pain can offer diagnostic clues.
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Cancer patients often suffer from pain and most will be prescribed μ-opioids. μ-opioids are not satisfactory in treating cancer pain and are associated with multiple debilitating side effects. Recent studies show that μ and δ opioid receptors are separately expressed on IB4 (-) and IB4 (+) neurons, which control thermal and mechanical pain, respectively. In this study we investigated IB4 (+) and IB4 (-) neurons in mechanical and thermal hypersensitivity in an orthotopic mouse oral cancer model. We used a δ opioid receptor agonist and a P2X(3) antagonist to target IB4 (+) neurons and to demonstrate that this subset plays a key role in cancer-induced mechanical allodynia, but not in thermal hyperalgesia. Moreover, selective removal of IB4 (+) neurons using IB4-saporin impacts cancer-induced mechanical but not thermal hypersensitivity. Our results demonstrate that peripherally administered pharmacological agents targeting IB4 (+) neurons, such as a selective δ-opioid receptor agonist or P2X(3) antagonist, might be useful in treating oral cancer pain. ⋯ To clarify the mechanisms of oral cancer pain, we examined the differential role of IB4 (+) and IB4 (-) neurons. Characterization of these 2 subsets of putative nociceptors is important for further development of effective clinical cancer pain relief.