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Gene variants may contribute to individual differences in the experience of pain and the efficacy and reward of treatments. We explored gene variation in opioid-naïve and opioid-consuming patients undergoing elective lower extremity total joint replacement. We focused on 3 gene pathways including prostaglandin, gamma-aminobutyric acid (GABA)-ergic reward, and hepatic metabolism pathways. We report that for genes with possible or probable deleterious impact in these 3 pathways, opioid consumers had more gene variants than opioid-naïve patients (median 3 vs 1, P = .0092). We conclude that chronic opiate users may have genetic susceptibility to altered responses in reward/dependency and pain/inflammation pathways.

Background Although most severe peripheral nerve injuries result from high-speed mechanisms, there is no laboratory model to replicate this clinical condition. Objective To qualitatively and quantitatively describe microanatomical injury of rapid stretch. Methods The sciatic nerves of 36 Sprague-Dawley rats were subjected to rapid-stretch nerve injury, using fixed-direction strain produced via constrained weight drop applied to an intact nerve. Nerve injury severity was categorized by biomechanical parameters. Injury to nerve microarchitecture was quantified with serial longitudinal sectioning, with specific focus on the endoneurium, perineurium, and epineurium. Results Four grades of stretch injury severity were determined by mathematical cluster analysis: sham, elastic stretch, inelastic stretch, and stretch rupture. Two patterns of injury to endoneurial architecture were quantified: loss of fiber undulation (straightened fibers) and rupturing of individual fibers ("microruptures"). Straightening of nerve fibers was the earliest accommodation to stretch injury and accounted for elongation during elastic stretch. Microruptures were distributed along the length of the nerve and were more severe and involved greater volume of the nerve at higher biomechanical severity. Epineurium and perineurium disruption increased in frequency with progressive injury severity, yet did not predict transition from one injury grade to another (P = .3), nor was it a hallmark of severe injury. Conversely, accumulation of microruptures provided strong correlation to nerve injury severity (Pearson's R = .9897) and progression to mechanical failure. Conclusion Nerve architecture is injured in a graded fashion during stretch injury, which likely reflects tissue biomechanics. This study suggests new considerations in the theoretical framework of nerve stretch trauma.

Opioids may influence inflammation. We compared genes associated with pain and inflammation in patients who consumed opioids (3-120 mg of oral morphine equivalents per day) with those who did not for differential expression. White blood cells were assayed in 20 patients presenting for total lower extremity joint replacement. We focused on messenger ribonucleic acid expression of complement proteins. We report that the expression of a complement inhibitor, complement 4 binding protein A, was reduced, and the expression of a complement activator, complement factor D, was increased in opioid-consuming patients. We conclude that opioid consumption may influence expression of complement activators and inhibitors.

Background Remifentanil is an injectable opioid that is metabolized rapidly at a constant rate by plasma esterases. This supports its use as an analgesic for short-term, but painful, procedures in a wide range of patients. The aim of this study was to explore the feasibility and safety of administering remifentanil via inhalation. Our hypothesis was that inhaled remifentanil would be absorbed rapidly, pharmacologically active, rapidly cleared, and noninjurious to rodent airways and lungs. Methods Rats were exposed to remifentanil aerosol (100-2000 μg/mL) for varying times (1-5 minutes). Analgesia was quantified as a function of dose and time by measuring time to tail flick in response to a painful stimulus. Remifentanil was measured in blood using liquid chromatography-tandem mass spectrometry. Pulmonary mechanics and histology were assessed in mice for the evidence of adverse effects after acute and repeated (subacute) dosing. Results Exposure of rats to remifentanil aerosols produced dose-dependent analgesia within 2 minutes, which was sustained for the exposure period. Subsequently, the rats experienced rapid and complete recovery with a return to baseline tail flick response to a painful stimulus within 5 minutes. Analgesia mirrored the concentration profile of remifentanil in blood, and the animals were not affected adversely by repeated dosing. Pulmonary mechanics measurements in mice indicated that remifentanil was nonirritating and that the nasal and respiratory tissues of rats were free of significant morphological changes. Conclusions Remifentanil delivered by inhalation is rapidly absorbed, pharmacologically active, rapidly cleared, and noninjurious to respiratory tissues in rodents.

Objective Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) are characterized by debilitating fatigue, yet evaluation of this symptom is subjective. We examined metabolite-detecting, adrenergic, and immune gene expression (messenger ribonucleic acid [mRNA]) in patients with CFS (n = 22) versus patients with MS (n = 20) versus healthy controls (n = 23) and determined their relationship to fatigue and pain before and after exercise. Methods Blood samples and fatigue and pain ratings were obtained at baseline and 0.5, 8, 24, and 48 hours after sustained moderate exercise. Leukocyte mRNA of four metabolite-detecting receptors (acid-sensing ion channel 3, purinergic type 2X4 and 2X5 receptors, and transient receptor potential vanilloid type 1) and four adrenergic (α-2a, β-1, and β-2 receptors and catechol-O-methyltransferase) and five immune markers (CD14, toll-like receptor 4 [TLR4], interleukin [IL] 6, IL-10, and lymphotoxin α) was examined using quantitative polymerase chain reaction. Results Patients with CFS had greater postexercise increases in fatigue and pain (10-29 points above baseline, p Conclusions Postexercise mRNA increases in metabolite-detecting receptors were unique to patients with CFS, whereas both patients with MS and patients with CFS showed abnormal increases in adrenergic receptors. Among patients with MS, greater fatigue was correlated with blunted immune marker expression.

The effects of spinal lesions on reactions of rats to nociceptive electrocutaneous stimulation (ES) were evaluated by measuring the speed of operant escape responses, the magnitude of hindlimb flexion reflexes and the amplitude of reflex vocalizations. ES intensities ranging from 0.1 to 0.8 mA were delivered to either hindpaw of rats that were trained to terminate stimulation (perform an escape response) with one forelimb. Unilateral thoracic lesions within the lateral column were produced by surgically transecting axons, with or without insertion of blood-soaked Gelfoam into the lesion cavity. The latter procedure was intended to standardize and maximize hemotoxic damage to the gray matter at the lesion site. The speed of conscious escape responses to all intensities was reduced contralaterally and to comparable extents following each type of lesion. Involvement of mid-lateral axons was an important determinant of contralateral deficits in escape responding. Escape speed for ipsilateral stimulation was not affected by the lesion without intentional insertion of blood but was reliably increased by addition of blood to the lesion site. Flexion reflexes were substantially decreased contralaterally and slightly decreased ipsilaterally, in accordance with previous investigations of anterolateral lesion effects in monkeys. Early (reflex) vocalizations were essentially eliminated for stimulation contralateral to the lesions, but vocalizations following ipsilateral stimulation were little affected. Postoperative variations in behavioral responsivity over time were not accounted for by pre- and post-estrous stages of the estrous cycle. The principal finding of this study is that hemotoxic accompaniments of a spinal lesion produce hyperalgesia for nociceptive stimulation applied ipsilaterally to segments well caudal to the lesion. This finding indicates that hemotoxic injury of the gray matter near an anterolateral spinal lesion enhances the excitation of certain rostral structures that receive nociceptive information.