Highlights
- •Repeated injections of hypertonic saline produced a persistent, bilateral muscular hypersensitivity.
- •Cutaneous cold allodynia was also elicited following the repeated injections.
- •The elicited hypersensitivity occurred independently of the acute pain response to hypertonic saline.
- •Minocycline pre-treatment prevented the development of the hypersensitive response.
- •Minocycline did not change any aspect of the acute hypertonic saline pain response
Abstract
Minocycline, a glial suppressor, prevents behavioral hypersensitivities in animal
models of peripheral nerve injury. However, clinical trials of minocycline in human
studies have produced mixed results. This study addressed 2 questions: can repeated
injections of hypertonic saline (HS) in humans induce persistent hypersensitivity?
Can pretreatment with minocycline, a tetracycline antibiotic with microglial inhibitory
effects, prevent the onset of hypersensitivity? Twenty-seven healthy participants
took part in this double-blind, placebo-controlled study, consisting of 6 test sessions
across 2 weeks. At the beginning of every session, pressure-pain thresholds of the
anterior muscle compartment of both legs were measured to determine the region distribution
and intensity of muscle soreness. To measure changes in thermal sensitivity in the
skin overlying the anterior muscle compartment of both legs, quantitative sensory
testing was used to measure the cutaneous thermal thresholds (cold sensation, cold
pain, warm sensation, and heat pain) and a mild cooling stimulus was applied to assess
the presence of cold allodynia. To induce ongoing hypersensitivity, repeated injections
of HS were administered into the right tibialis anterior muscle at 48-hour intervals.
In the final 2 sessions (days 9 and 14), only sensory assessments were done to plot
the recovery after cessation of HS administrations and drug washout. By day 9, nontreated
participants experienced a significant bilateral increase in muscle soreness (P < .0001), accompanied by the emergence of bilateral cold allodynia in 44% of participants,
thus confirming the effectiveness of the model. Placebo-treated participants experienced
a bilateral 35% alleviation in muscle soreness (P < .0001), with no changes to the prevalence of cold allodynia. In contrast, minocycline-treated
participants experienced a bilateral 70% alleviation in muscle soreness (P < .0001), additionally, only 10% of minocycline-treated participants showed cold
allodynia. This study showed that repeated injections of HS can induce a hypersensitivity
that outlasts the acute response, and the development of this hypersensitivity can
be reliably attenuated with minocycline pretreatment.
Perspective
Four repeated injections of HS at 48-hour intervals induce a state of persistent hypersensitivity
in healthy human participants. This hypersensitivity was characterized by bilateral
muscular hyperalgesia and cutaneous cold allodynia, symptoms commonly reported in
many chronic pain conditions. Minocycline pretreatment abolished the development of
this state.
Key words
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Article info
Publication history
Published online: April 07, 2017
Accepted:
March 21,
2017
Received in revised form:
March 12,
2017
Received:
August 12,
2016
Footnotes
The authors have no conflicts of interest to declare.
Identification
Copyright
Crown Copyright © 2017 Published by Elsevier Inc. on behalf of the American Pain Society
