Systemic administration of a β2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity

Beta 2 adrenergic receptor (beta 2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of beta 2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the beta 2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of beta 2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined beta 2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of beta 2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of beta 2-AR agonists to models of surgical injury.

Automated summary

Activation of Beta 2 adrenergic receptors has been shown to alleviate postoperative mechanical hypersensitivity, with more significant effects in depleted rats. Treatment with clenbuterol can reduce mechanical hypersensitivity, but has no significant impact on the speed of postoperative recovery. The study suggests that Beta 2 adrenergic receptors play a regulatory role in postoperative hypersensitivity in the nervous system.