When all subjects were analyzed without partitioning into high- and low-sensitizers, there were no significant difference between SHAs following naloxone infusion (median [95% CI]: 0 [0C0

When all subjects were analyzed without partitioning into high- and low-sensitizers, there were no significant difference between SHAs following naloxone infusion (median [95% CI]: 0 [0C0.3] cm2), compared to the placebo infusion (median [95% CI]: 0 [0C0] cm2; Wilcoxon MK-4827 (Niraparib) signed-rank test: P = 0.215). number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile (high-sensitizers [n = 20]) and the lower quartile (low-sensitizers [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics MK-4827 (Niraparib) revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between high-sensitizers and low-sensitizers (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for high-sensitizers (P 0.001), but not low-sensitizers (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted. Introduction The endogenous opioid analgesia system can be impaired or altered in chronic pain conditions [1C4], playing a putative pathophysiological role in the transition from acute to chronic pain [5C7]. Naloxone and naltrexone are -opioid-receptor (MOR) inverse agonists [6] used in experimental research to determine MK-4827 (Niraparib) the activity of the endogenous opioid analgesia system [8, 9]. Naloxone produces either hypoalgesic or hyperalgesic responses to nociceptive stimulation, depending on the dose administered [10]. Studies in rodents indicate that endogenous MOR constitutive activity masks a process called latent sensitization [6], defined as an increased responsiveness of nociceptive neurons to afferent input induced by either injury, chronic opioid administration, or physiological stress. Latent sensitization can persist in the absence of behavioral signs of hypersensitivity and outlasts the duration of tissue healing. It can be revealed upon administration of an opioid receptor inverse agonist, leading to reinstatement of hyperalgesia in rodents [5, 6, 11, RAB21 12]. In an initial randomized, controlled, crossover trial design, we reported that an intravenous dose of naloxone (21 microg/kg), delivered 72 h after a cutaneous heat injury (CHI), failed to reinstate hyperalgesia in healthy human subjects [13]. In a follow-up trial using a higher dose of naloxone (2 mg/kg), four out of twelve subjects demonstrated reinstatement of hyperalgesia [14]. Reinstatement of latent sensitization, if consistently present in humans may constitute one of the basic trigger mechanisms in development of chronic pain states, e.g. chronic postsurgical pain. Furthermore, we noticed that the subjects developing reinstatement of hyperalgesia were subjects with larger initial areas of secondary hyperalgesia (SHA), leading us to hypothesize that latent sensitization occurs more often in high-sensitizers as compared to low-sensitizers. If the hypothesis is validated, the enriched design could be used in future trials to determine indicators of vulnerability to chronic postsurgical pain [14]. The objectives of the current trial were, first, to replicate [15] our previous latent sensitization trial applying a larger sample size. Second, using an enriched enrollment design, to examine whether high-sensitizers express larger hyperalgesia areas after a naloxone challenge than low-sensitizers. Materials and methods Trial management The trial was approved by the MK-4827 (Niraparib) Committee of Health Research Ethics of the Capital Region (H-15018869), the Danish Medicines Agency (2015C005426C19), and the Data Inspection Authority of the Capital.