Aim: to investigate the factors of bacterial virulence of oral microbiotopes against the background of long-term experimental action of an opioid analgesic.
Materials and Methods:The study was performed on 72 white outbred rats, which were injected “Nalbuphine” with a gradual increase in dose for 12 weeks.
The microbial composition and virulence factors of bacteria in the microbiotopes of the oral cavity were studied.
Results: At the end of the 4th week of opioid exposure, the appearance of hemolytic escherichia was noted. At the end of the 8th week the appearance of
capsular bacteria Klebsiella was registered, as a virulence factor. The production of staphylococcal virulence factors – lecithinase, was noted. At the end of the
12th week of opioid use, the appearance of phycomycete fungi was noted, Gram-negative diplococci, Klebsiella, Hemolytic Escherichia coli and Pseudomonas
aureginosa. These changes indicated the development of dysbiotic changes, as well as the gradual formation of foci of the inflammatory process in the oral cavity.
   Conclusions: In the short-term stages of opioid exposure, changes in biocenoses were manifested in an increase in the contamination of certain types of
microorganisms. In the long-term effects of the opioid, the activation of bacterial elements of the microbiocenosis was revealed, which were characterized by
increased expression of virulence factors. At the later stages of opioid exposure, the predominance of gram-negative microflora and the activation of cytotoxic action against the background of suppressed activity of the body’s protective response were established.
KEY WORDS: experiment, oral cavity, microbiotopes, opioid, rats, microorganisms, virulence factors

Over the last decade, there has been an increase in illegal drug use and uncontrolled opioid abuse in patients with chronic pain, which is associated with unintentional trauma and is a major risk factor for tolerance and withdrawal, leading to overdose and death [1-5]. The attention of scientists in various fields of medicine is focused on the study of changes in organs and systems under the influence of drugs, in particular, both in clinical and experimental
areas [6-9]. In clinical studies it is indicated that when exposed to opioids there are signs of immunosuppression, which cause an increased risk of infectious diseases and the development of inflammation [5, 10, 11]. Toxic effects of drugs are manifested in all organs and systems, which
may have an indirect or direct effect on the organs of the oral cavity [6, 12-15]. The question of the role of bacterial flora in the etiology and initiation of periodontal disease is certainly actively studied as the improvement of microbiological methods and the accumulation of research results [16-19]. Today,
one of the main hypotheses remains that dental plaque microorganisms are a determining factor in the development and progression of the inflammatory process in the periodontium, which provoke the inflammatory process and directly affect the microbial status of the oral cavity [20- 23].There is also evidence that the role of microorganisms in the development of periodontitis is unclear, although some bacterial pathogens alone or as part of microbial groups may be particularly important [24]. Therefore, in order to prevent the development of periodontal disease and the occurrence of infectious foci in the oral cavity caused by bacterial biopellicle, it is important to determine the etiology and pathogenesis of this pathology in experimental animal models in order to further extrapolate these data to the clinic [25]. However, the relationship between the species and quantitative composition of the microbiota of tooth surface in the gingival margin and the development and progression of inflammation in the gingival mucosa under action of the opioid are controversial and needs further study using modern methods of microbiological research in the experiment.

ABSTRACT 
Aim: To study changes of dental biofilm microbiota composition during experimental opioid exposure, after its withdrawal and when using of complex drug correction.
Materials and Methods: Microbiological studies (48 rats) included microscopic and bacteriological methods, as well as determination of antibiotic susceptibility of microbial isolates. Ceftriaxone and pentoxifylline were used to correction the changes.
Results: The action of opioid for 10 weeks caused considerable changes in the microbiocenosis, which was illustrated by a significant increasing of the opportunistic pathogens quantitative indicators and the emergence of pathogenic microbiota. Changes in the microbiocenosis at 6 weeks of opioid exposure and after its withdrawal for 4 weeks were expressed in the appearance of pathogenic microbiota and the absence of significant differences in quantitative indicators of saprophytic and opportunistic microflora compared to similar indicators in animals with 10 weeks opioid exposure. This indicated a slow progression of dysbiotic changes and the inflammatory process in the oral cavity of rats.
Conclusions: After 10 weeks of experiment with opioid administration for 6 weeks and the use of ceftriaxone and pentoxifylline on the background of 4-week opioid withdrawal, a significant reduction of quantitative indicators of opportunistic bacteria and elimination of pathogenic species of microorganisms was determined. The use of complex drug correction on the background of 10 weeks of opioid exposure led to a significant reduction in the quantitative indicators of opportunistic pathogens and contributed to the elimination of most pathogenic species of microbiota under the action of ceftriaxone.
KEY WORDS: oral cavity, rats, opioid exposure, microbiota, drug correction