Distinct pain control in the spinal dorsal horn via astrocytic α- and β-adrenoceptors

Pain transmission in the spinal dorsal horn (SDH) is powerfully controlled by descending neurons from the brain. One major neurotransmitter of the descending pathways is noradrenaline (NA). Traditionally, NA is known to produce an analgesic effect, but we recently demonstrated that NA also induces a pronociceptive effect via α1A-adrenoceptors (α1A-ARs) in SDH astrocytes expressing Hes5. Therefore, the mechanism for bidirectional modulation by NA is entirely unknown. In this study, we found that intrathecal injection of NA at a low dose induced mechanical hypersensitivity, which required α1A-ARs in Hes5+ astrocytes. On the other hand, at a high dose of intrathecal NA, the hypersensitivity disappeared. Interestingly, this effect of the high dose of NA was not affected by lacking α1A-ARs in Hes5+ astrocytes, but was prevented by pharmacological inhibition of spinal β1-ARs or genetic knockout of astrocytic β1-ARs. Furthermore, mechanical hypersensitivity by chronic stress was suppressed and exacerbated by astrocytic α1A- and β1-AR-knockout, respectively. Our findings suggest that the bidirectional pain control by spinal NA is dependent on the levels of NA and the different types of astrocytic adrenoceptors.