title: Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice.
abstract: The use of botulinum neurotoxin type A (BoNT/A) against pain, with emphasis for its possible use in alleviating chronic pain, still represents an outstanding challenge for experimental research. In this study, we examined the effects of BoNT/A on morphine-induced tolerance during chronic morphine treatment in neuropathic CD1 mice subjected to sciatic nerve lesion according to the Chronic Constriction Injury (CCI) model of neuropathic pain. We measured the effects of BoNT/A on CCI-induced allodynia and hyperalgesia and on the expression of glial fibrillary acidic protein (GFAP, marker of astrocytes), complement receptor 3/cluster of differentiation 11b (CD11b, marker of microglia), and neuronal nuclei (NeuN) at the spinal cord level. We also analyzed the colocalized expression of GFAP, CD11b and NeuN with phosphorylated p-38 mitogen-activated protein kinase and with μ-opioid receptor (MOR). A single intraplantar injection of BoNT/A (15 pg/paw) into the injured hindpaw, the day before the beginning of chronic morphine treatment (9 days of twice daily injections of 40 mg/kg morphine), was able to counteract allodynia and enhancement of astrocytes expression/activation induced by CCI. In addition, BoNT/A increased the analgesic effect of morphine and countered morphine-induced tolerance during chronic morphine treatment. These effects were accompanied, in neurons, by re-expression of MORs that had been reduced by repeated morphine administration. The combinatory effects of BoNT/A and morphine could have relevant therapeutic implications for sufferers of chronic pain who could benefit of pain relief reducing tolerance due to repeated treatment with opiates.
authors: CNR - National Research Council of Italy, Cell Biology and Neurobiology Institute/IRCCS - Santa Lucia Foundation, Rome, Italy.
authors: Valentina
authors: V
authors: Vacca
authors: Sara
authors: S
authors: Marinelli
authors: Siro
authors: S
authors: Luvisetto
authors: Flaminia
authors: F
authors: Pavone
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019274:Botulinum Toxins, Type A / Q000627:therapeutic use*; D039481:CD11b Antigen / Q000378:metabolism; D059350:Chronic Pain / Q000188:drug therapy; D004357:Drug Synergism; D004361:Drug Tolerance / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000502:physiology*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D009020:Morphine / Q000627:therapeutic use*; D009457:Neuroglia / Q000187:drug effects*; D009465:Neuromuscular Agents / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000276:immunology / Q000523:psychology; D010812:Physical Stimulation; D017450:Receptors, Opioid, mu / Q000096:biosynthesis* / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology
chemical_list: D000701:Analgesics, Opioid; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D009465:Neuromuscular Agents; D017450:Receptors, Opioid, mu; D009020:Morphine; D019274:Botulinum Toxins, Type A