Abstract
Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited 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 (47°C, 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 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.
Highlights
The endogenous opioid analgesia system can be impaired or altered in chronic pain conditions [1,2,3,4], playing a putative pathophysiological role in the transition from acute to chronic pain [5,6,7]
Naloxone and naltrexone are μ-opioid-receptor (MOR) inverse agonists [6] used in experimental research to determine the activity of the endogenous opioid analgesia system [8, 9]
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]
Summary
The endogenous opioid analgesia system can be impaired or altered in chronic pain conditions [1,2,3,4], playing a putative pathophysiological role in the transition from acute to chronic pain [5,6,7]. Naloxone and naltrexone are μ-opioid-receptor (MOR) inverse agonists [6] used in experimental research to determine the activity of the endogenous opioid analgesia system [8, 9]. 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, 12]
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