The journal of pain : official journal of the American Pain Society
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Diffuse Noxious Inhibitory Controls (DNIC) involves application of a noxious stimulus outside the testing site to produce analgesia. In human subjects with a variety of chronic pain conditions, DNIC is less effective; however, in animal studies, DNIC is more effective after tissue injury. While opioids are involved in DNIC analgesia, the pathways involved in this opioid-induced analgesia are not clear. The aim of the present study was to test the effectiveness of DNIC in inflammatory muscle pain, and to study which brainstem sites mediate DNIC- analgesia. Rats were injected with 3% carrageenan into their gastrocnemius muscle and responses to cutaneous and muscle stimuli were assessed before and after inflammation, and before and after DNIC induced by noxious heat applied to the tail (45 °C and 47 °C). Naloxone was administered systemically, into rostral ventromedial medulla (RVM), or bilaterally into the medullary reticularis nucleus dorsalis (MdD) prior to the DNIC-conditioning stimuli. DNIC produced a similar analgesic effect in both acute and the chronic phases of inflammation reducing both cutaneous and muscle sensitivity in a dose-dependent manner. Naloxone systemically or microinjected into the MdD prevented DNIC-analgesia, while naloxone into the RVM had no effect on DNIC analgesia. Thus, DNIC analgesia involves activation of opioid receptors in the MdD. ⋯ The current study shows that DNIC activates opioid receptors in the MdD, but not the RVM, to produce analgesia. These data are important for understanding clinical studies on DNIC as well as for potential treatment of chronic pain patients.
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Evidence suggests that gamma-aminobutyric acid (GABA) signalling in the basolateral amygdala (BLA) is involved in pain, fear, and fear-conditioned analgesia (FCA). In this study, we investigated the effects of intra-BLA administration of the GABA(A) receptor agonist muscimol on the expression of conditioned-fear, formalin-evoked nociception, and fear-conditioned analgesia in rats, and the associated alterations in brain regional expression of the immediate early gene product and marker of neuronal activity, c-Fos. Formalin-evoked nociceptive behavior, conditioned-fear and fear-conditioned analgesia were apparent in animals receiving intra-BLA saline. Intra-BLA muscimol suppressed fear behavior and prevented fear-conditioned analgesia, but had no significant effect on the expression of formalin-evoked nociception. The suppression of fear behavior by intra-BLA muscimol was associated with increased c-Fos expression in the central nucleus of the amygdala (CeA) and throughout the periaqueductal grey (PAG). These intra-BLA muscimol-induced increases in c-Fos expression were abolished in rats receiving intraplantar formalin injection. These data suggest that alterations in neuronal activity in the CeA and PAG as a result of altered GABAergic signalling in the BLA may be involved in the behavioral expression of fear and associated analgesia. Furthermore, these alterations in neuronal activity are susceptible to modulation by formalin-evoked nociceptive input in a state-dependent manner. ⋯ The expression of learned fear and associated analgesia are under the control of GABA(A) receptors in the basolateral amygdala, through a mechanism which may involve altered neuronal activity in key components of the descending inhibitory pain pathway. The results enhance our understanding of the neural mechanisms subserving fear-pain interactions.