The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an "analgesia system" is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands.Descending control arises from a number of supraspinal sites, including the midline periaqueductral gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensorydiscriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.

Translational control through the mammalian target of rapamycin (mTOR) is critical for synaptic plasticity, cell growth, and axon guidance. Recently, it was also shown that mTOR signaling was essential for the maintenance of the sensitivity of subsets of adult sensory neurons. Here, we show that persistent pain states, but not acute pain behavior, are substantially alleviated by centrally administered rapamycin, an inhibitor of the mTOR pathway. We demonstrate that rapamycin modulates nociception by acting on subsets of primary afferents and superficial dorsal horn neurons to reduce both primary afferent sensitivity and central plasticity. We found that the active form of mTOR is present in a subpopulation of myelinated dorsal root axons, but rarely in unmyelinated C-fibers, and heavily expressed in the dorsal horn by lamina I/III projection neurons that are known to mediate the induction and maintenance of pain states. Intrathecal injections of rapamycin inhibited the activation of downstream targets of mTOR in dorsal horn and dorsal roots and reduced the thermal sensitivity of A-fibers. Moreover, in vitro studies showed that rapamycin increased the electrical activation threshold of A␦-fibers in dorsal roots. Together, our results imply that central rapamycin reduces neuropathic pain by acting both on an mTOR-positive subset of A-nociceptors and lamina I projection neurons and suggest a new pharmacological route for therapeutic intervention in persistent pain states.

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states.

The central neural pathways involved in fear-evoked behaviour are highly conserved across mammalian species, and there is a consensus that understanding them is a fundamental step towards developing effective treatments for emotional disorders in man. The ventrolateral periaqueductal grey (vlPAG) has a well-established role in fear-evoked freezing behaviour. The neural pathways underlying autonomic and sensory consequences of vlPAG activation in fearful situations are well understood, but much less is known about the pathways that link vlPAG activity to distinct fear-evoked motor patterns essential for survival. In adult rats, we have identified a pathway linking the vlPAG to cerebellar cortex, which terminates as climbing fibres in lateral vermal lobule VIII (pyramis). Lesion of pyramis input–output pathways disrupted innate and fear-conditioned freezing behaviour. The disruption in freezing behaviour was strongly correlated to the reduction in the vlPAG-induced facilitation of α-motoneurone excitability observed after lesions of the pyramis. The increased excitability of α-motoneurones during vlPAG activation may therefore drive the increase in muscle tone that underlies expression of freezing behaviour. By identifying the cerebellar pyramis as a critical component of the neural network subserving emotionally related freezing behaviour, the present study identifies novel neural pathways that link the PAG to fear-evoked motor responses.

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert analgesic effects by inhibiting peripheral cyclooxygenases (COXs).It is now clear that these drugs also have central actions that include the modulation of descending control of spinal nociception from the midbrain periaqueductal gray (PAG). Descending control is a powerful determinant of the pain experience and is thus a potential target for analgesic drugs, including COX inhibitors. Noxious information from the periphery is conveyed to the spinal cord in A-and C-fiber nociceptors, which convey different qualities of the pain signal and have different roles in chronic pain. This in vivo study used different rates of skin heating to preferentially activate A-or C-heat nociceptors to further investigate the actions of COX inhibitors and prostaglandins in the PAG on spinal nociceptive processing. The results significantly advance our understanding of the central mechanisms underlying the actions of NSAIDs and prostaglandins by demonstrating that (1) in the PAG, it is COX-1 and not COX-2 that is responsible for acute antinociceptive effects of NSAIDs in vivo; (2) these effects are only evoked from the opioid-sensitive ventrolateral PAG; and (3) prostaglandins in the PAG exert tonic facilitatory control that targets C-rather than A-fiber-mediated spinal nociception. This selectivity of control is of particular significance given the distinct roles of A-and C-nociceptors in acute and chronic pain. Thus, effects of centrally acting prostaglandins are pivotal, we suggest, to both the understanding of nociceptive processing and the development of new analgesic drugs.