Participation of pro- and anti-nociceptive interleukins in botulinum toxin A-induced analgesia in a rat model of neuropathic pain.
Botulinum neurotoxin serotype A (BoNT/A) shows antinociceptive properties, and its clinical applications in pain therapy are continuously increasing. BoNT/A specifically cleaves SNAP-25, which results in the formation of a non-functional SNARE complex, thereby potently inhibiting the release of neurotransmitters and neuropeptides, including those involved in nociception. The aim of the present study was to determine the effects of BoNT/A (300pg/paw) on pain-related behavior and the levels of glial markers and interleukins in the spinal cord and dorsal root ganglia (DRG) after chronic constriction injury (CCI) to the sciatic nerve in rats. Glial activity was also examined after repeated intraperitoneal injection of minocycline combined with a single BoNT/A injection. Our results show that a single intraplantar BoNT/A injection did not influence motor function but strongly diminished pain-related behaviors in naïve and CCI-exposed rats. Additionally, microglial inhibition using minocycline enhanced the analgesic effects of BoNT/A. Western blotting results suggested that CCI induces the upregulation of the pronociceptive proteins IL-18, IL-6 and IL-1β in the ipsilateral lumbar spinal cord and DRG, but no changes in the levels of the antinociceptive proteins IL-18BP, IL-1RA and IL-10 were observed. Interestingly, BoNT/A injection suppressed the CCI-induced upregulation of IL-18 and IL-1β in the spinal cord and/or DRG and increased the levels of IL-10 and IL-1RA in the DRG. In summary, our results suggest that BoNT/A significantly attenuates pain-related behavior and microglial activation and restores the neuroimmune balance in a CCI model by decreasing the levels of pronociceptive factors (IL-1β and IL-18) and increasing the levels of antinociceptive factors (IL-10 and IL-1RA) in the spinal cord and DRG.
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Magdalena
M
Zychowska
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Ewelina
E
Rojewska
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Wioletta
W
Makuch
CNR, Institute of Cell Biology and Neurobiology, IRCCS, Santa Lucia Foundation, Roma, Italy.
Siro
S
Luvisetto
CNR, Institute of Cell Biology and Neurobiology, IRCCS, Santa Lucia Foundation, Roma, Italy.
Flaminia
F
Pavone
CNR, Institute of Cell Biology and Neurobiology, IRCCS, Santa Lucia Foundation, Roma, Italy.
Sara
S
Marinelli
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Barbara
B
Przewlocka
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland. Electronic address: joasia272@onet.eu.
Joanna
J
Mika
D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D019274:Botulinum Toxins, Type A / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D005106:Exploratory Behavior / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D059225:Nociception / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000700:Analgesics; D015415:Biomarkers; D007378:Interleukins; D019274:Botulinum Toxins, Type A; D008911:Minocycline
Botulinum neurotoxin A; Glia; Interleukins; Minocycline; Neuropathic pain model