Neurotropin® ameliorates chronic pain associated with scar formation in a mouse model: A gene expression analysis of the inflammatory response.

Background: Scar formation after trauma and surgery involves an inflammatory response and can lead to the development of chronic pain. Neurotropin® (NTP) is a nonprotein extract of inflamed skin of rabbits inoculated with vaccinia virus. It has been widely used for the treatment of chronic pain. However, the in vivo effects of NTP on painful scar formation have not been determined. To investigate the molecular mechanisms underlying the effects of NTP on the inflammatory response, we evaluated gene expression in the scar tissues and dorsal root ganglions (DRGs) of mice administered NTP and control mice. Methods and results: Mice injected with saline or NTP were used as controls; other mice were subjected to surgery on the left hind paw to induce painful scar formation, and then injected with saline or NTP. Hind paw pain was evaluated by measuring the threshold for mechanical stimulation using the von Frey test. The paw withdrawal threshold gradually returned to pre-operative levels over 4 weeks post-operation; NTP-treated mice showed a significantly shortened recovery time of approximately 3 weeks, suggesting that NTP exerted an analgesic effect in this mouse model. Total RNA was extracted from the scarred hind paw tissues and DRGs were collected 1 week post-operation for a microarray analysis. Gene set enrichment analysis revealed that the expression of some gene sets related to inflammatory responses was activated or inhibited following surgery and NTP administration. Quantitative real-time reverse transcription-polymerase chain reaction analysis results for several genes were consistent with the microarray results. Conclusion: The administration of NTP to the hind paws of mice with painful scar formation following surgery diminished nociceptive pain and reduced the inflammatory response. NTP inhibited the expression of some genes involved in the response to surgery-induced inflammation. Therefore, NTP is a potential therapeutic option for painful scar associated with chronic pain.

Partner Loss in Monogamous Rodents: Modulation of Pain and Emotional Behavior in Male Prairie Voles.

OBJECTIVE: Pain is modulated by psychosocial factors, and social stress-induced hyperalgesia is a common clinical symptom in pain disorders. To provide a new animal model for studying social modulation of pain, we examined pain behaviors in monogamous prairie voles experiencing partner loss. METHODS: After cohabitation with novel females, males (n = 79) were divided into two groups on the basis of preference test scores. Half of the males of each group were separated from their partner (loss group), whereas the other half remained paired (paired group). Thus, males from both groups experienced social isolation. Open field tests, plantar tests, and formalin tests were then conducted on males to assess anxiety and pain-related behaviors. RESULTS: Loss males showing partner preferences (n = 20) displayed a significant increase in anxiety-related behavior in the open-field test (central area/total distance: 13.65% [1.58%] for paired versus 6.45% [0.87%] for loss; p < .001), a low threshold of thermal stimulus in the plantar test (withdrawal latencies: 9.69 [0.98] seconds for paired versus 6.15 [0.75] seconds for loss; p = .037), and exacerbated pain behaviors in the formalin test (total number of lifts: 40.33 [4.46] for paired versus 54.42 [1.91] for loss; p = .042) as compared with paired males (n = 20). Thermal thresholds in the plantar test significantly correlated with anxiety-related behavior in the open-field test (r = 0.64). No such differences were observed in the males that did not display partner preferences (r = 0.15). CONCLUSIONS: Results indicate that social bonds and their disruption, but not social housing without bonding followed by isolation, modulate pain and emotion in male prairie voles. The prairie vole is a useful model for exploring the neural mechanisms by which social relationships contribute to pain and nociceptive processing in humans.

A Pusher and a Clip Applied to Hind Paws Under Isoflurane Sedation to Evaluate Neuropathic Pain in a CCI Model.

Rodent behavior assessments have been developed to evaluate pain. However, their fidgety activity and reactivity to human contact make it hard to activate animals in a consistent manner and get uniform and trustworthy responses. The present study was performed on prairie voles (aged 8 weeks). Sham (7 male prairie voles) and chronic constriction injury (CCI) (8 male prairie voles) rodents were investigated before surgery and four and seven days later. Each animal was assessed for nociceptive behavior. Pressure and mechanical threshold tests were conducted by the application of three different pushers to the center of hind paws and arterial clips to the toes while sedated with isoflurane. The CCI affected right lower extremity prominently increased nociceptive behavior scores four and seven days after the experiment, and the CCI affected right hind paw prominently decreased pressure and mechanical threshold tests four and seven days after the experiment . The pressure and mechanical thresholds were relevant to the scorings of nociceptive behavior in CCI model animals.

Clipping Hind Paws Under Isoflurane Sedation as a Useful Tool for Evaluation of Chronic Pain in CCI Animals.

BACKGROUND: Several behavioral tests have been devised to assess pain in rodent models, one of which is the Chronic constriction injury (CCI) model of the sciatic nerve, including the sensitivity of the paw evaluated through reflex reactions to heat or mechanical stimuli. However, because of their high restless activity and responsiveness to humans, it is tough to give the moving animals consistent stimuli to get consistent and reliable reactions. METHODS: Experiments were performed on male C57BL/6J mice (aged eight weeks) and prairie voles (aged eight weeks). Sham animals (five mice and six prairie voles) and CCI animals (six mice and seven prairie voles) were tested before surgery, four days after, and seven days after surgery. Each animal was rated using a modified rating scale for the scoring of nociceptive behavior. The mechanical threshold test was administered by applying arterial clips to the base of toes under isoflurane-induced sedation. RESULTS: The right hind paw of the CCI administered side showed significant increases in the scores of nociceptive behavior on day 4 and day 7. The right hind paw of the CCI-administered side showed significant reductions in the mechanical threshold test on day 4 and day 7. CONCLUSIONS: The results of the mechanical threshold test were consistent with those of the scoring of nociceptive behavior in CCI model animals, and the method of using arterial clips under sedation was useful for the mechanical threshold test.