Plasticity in the Link between Pain-Transmitting and Pain-Modulating Systems in Acute and Persistent Inflammation.

Abstract

There is strong evidence that spinoparabrachial neurons in the superficial dorsal horn contribute to persistent pain states, and that the lateral parabrachial complex (PB) conveys relevant nociceptive information to higher structures. The role of PB itself in hyperalgesia and how it recruits descending facilitation has nevertheless received significantly less attention. The current study is a first step toward delineating the functional dynamics of PB and its link to descending control in acute and persistent inflammatory pain. In lightly anesthetized rats, we recorded behavioral withdrawal evoked by mechanical stimulation of the hindpaw and, simultaneously, the activity of identified pain-modulating neurons, "ON-cells" and "OFF-cells," in the rostral ventromedial medulla (RVM). This was done before and after the inactivation of PB, contralateral or ipsilateral to an inflamed paw [1 h, 1 d, or 5-6 d after intraplantar injection of Complete Freund's Adjuvant (CFA)]. The inactivation of contralateral, but not ipsilateral, PB interfered with nociceptive input to RVM under basal conditions, as well as in acute inflammation. By contrast, blocking ipsilateral, but not contralateral, PB in established inflammation interfered with behavioral hyperalgesia and ON-cell and OFF-cell responses. The lesioning of contralateral PB before CFA injection prevented this recruitment of ipsilateral PB in persistent inflammation. These experiments show that contralateral PB is required to initiate hyperalgesia, which is then maintained by ipsilateral PB, most likely in both cases via the engagement of pain-modulating neurons of the RVM.SIGNIFICANCE STATEMENT The lateral parabrachial complex (PB) relays nociceptive information to brain circuits that are important for the transmission and modulation of pain, but its specific role in persistent pain and engagement of descending control mechanisms has received relatively little attention. We show here that PB contralateral and ipsilateral to an inflammatory insult demonstrate different functions as inflammation persists, likely by engaging pain-facilitating neurons of the rostral ventromedial medulla. While the contralateral PB, the target of the major spinoparabrachial pathway, relays acute nociceptive information, the ipsilateral PB is recruited or unmasked in persistent inflammation to maintain hyperalgesia. These data point to plasticity in the PB itself or its direct and indirect connections with pain-modulating systems as central to the development and maintenance of persistent pain.