Lorne M. Mendell

BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs.

Brain‐derived neurotrophic factor (BDNF) is up‐regulated and released in the dorsal horn following peripheral inflammation and has therefore been implicated in spinal mechanisms of sensitization. Despite these observations, the mechanisms associated with such a role for BDNF are not yet fully determined. Here, we investigate the effect of BDNF on dorsal root‐evoked synaptic transmission in lamina II neurons. In a transverse spinal cord slice preparation from neonatal rats (P1–15), the whole cell patch‐clamp technique was used to record from these neurons. Brief application of BDNF (50–200 ng/mL) facilitated the evoked synaptic currents; they remained enhanced even after BDNF was washed out. A significant minority of cells was minimally affected by BDNF and consistent with this, not all neurons in lamina II were immunoreactive for the tyrosine kinase (trk) B receptor. No facilitation was elicited when N‐methyl‐d‐aspartate (NMDA) receptors were blocked with D‐APV, when the postsynaptic NMDA receptors were selectively blocked with intracellular MK‐801, or when postsynaptic neurons were loaded with BAPTA. Additionally, inhibiting phospholipase C (PLC) or protein kinase C (PKC) prior to BDNF application completely blocked facilitation. However, once synaptic current underwent BDNF‐induced facilitation, the PKC inhibitors failed to reverse the effect, suggesting that PKC is needed for initiation, but not maintenance of BDNF‐induced facilitation. These results demonstrate that BDNF functions at the spinal level to enhance synaptic efficacy in an NMDA receptor‐dependent manner and requires the action of the PLC/PKC pathway. This action of BDNF may contribute to central sensitization and exaggerated pain states.

Characteristics of nerve growth factor induced hyperalgesia in adult rats: dependence on enhanced bradykinin-1 receptor activity but not neurokinin-1 receptor activation

&NA; Treatment of adult rats with a single dose of nerve growth factor (NGF, 1 mg/kg, i.p.) results in a prolonged hypersensitivity to noxious thermal stimulation which becomes noticeable within 30 min of administration and lasts for several days. A significant mechanical hyperalgesia develops within 7 h following injection of NGF and persists for up to 7 days. In the present set of experiments we describe certain quantitative features of this hyperalgesia. The initial thermal hyperalgesia can be highly variable and is associated to some degree with the presence of an overt immunologic reaction. The mechanical hyperalgesia is reproducible enough to reveal a clear dependency on the dose of NGF. We also examined the pharmacological properties of the NGF‐induced hyperalgesia. The bradykinin BK1 receptor antagonist des‐Arg9[Leu8]BK transiently blocked the thermal hyperalgesia when injected 1 day after NGF administration whereas mechanical thresholds were further reduced under this protocol. The BK2 antagonist HOE 140 had no effect on this late NGF‐induced hyperalgesia. Injection of the neurokinin NK1 receptor antagonist CP‐96345 or its inactive enantiomer CP‐96344 one day after NGF both induced a transient block of NGF‐induced thermal hyperalgesia indicating a non‐specific effect rather than an action at NK1 receptors. This was confirmed by finding no reversal of NGF‐induced hyperalgesia by RP67580, another NK1 receptor blocker. These results suggest upregulation and activation of BK1 but not NK1 receptors as an additional, probably peripheral, mechanism for the late phase of NGF‐induced thermal hyperalgesia.

Mismatches between peripheral receptor type and central projections after peripheral nerve regeneration.

The central projections of axotomized fibers were assessed to investigate how well these matched the modality of the reinnervated receptor. Our results using intrafiber injection of horseradish peroxidase (HRP) and cord dorsum potentials evoked by intracellular stimulation of single afferents indicate that regenerating fibers can innervate inappropriate receptors. Mismatches included: (i) reinnervation of muscle receptors by cutaneous afferents, and vice versa; (ii) reinnervation of low threshold cutaneous receptors by nociceptive afferents; and (iii) reinnervation of slowly adapting receptors by fibers normally supplying rapidly adapting receptors.

Neurotrophin action on sensory neurons in adults: an extension of the neurotrophic hypothesis.

This brief review explores the action of neurotrophins on sensory neurons in adults. Neutralization of neurotrophins in adults does not cause sensory neurons to die as it does in prenatal animals. Thus they are not required as survival factors in adults. However, neurotrophins continue to play important roles in the postnatal development of sensory neurons. They also exert strong effects on the anatomy and physiology of these fibers after axotomy in adults. Here we review of the effects of NT-3 on spindle afferent fibers and NGF on nociceptive afferents and consider possible extension of the neurotrophic hypothesis to adults.

Diversity of neurotrophin action in the postnatal spinal cord

The expression of neurotrophins and their receptors in the adult spinal cord indicates that they have postnatal actions in addition to their well-known prenatal ones on axonal growth and cell survival. In this review we summarize evidence in support of mechanisms by which neurotrophins acutely modulate the response both of sensory neurons and of synapses within the spinal cord. The selective action of neurotrophins is achieved via restricted expression of high affinity trk receptors through which the neurotrophins act. Activation of trk receptors enhances the response of the vanilloid VR-1 receptor in nociceptive neurons leading to peripheral sensitization of the response to capsaicin or noxious heat. At synapses on motoneurons trk receptor activation enhances the response of NMDA receptors that in turn can increase the response of AMPA/kainate receptors on the same cell. Both of these sensitizing actions have a very rapid onset that is contrasted with slower neurotrophin effects on growth of axotomized afferents. It is likely that these different functional effects of neurotrophins reflect activation of different intracellular signaling pathways. These studies suggest mechanisms by which neurotrophins might be used to improve function of the damaged spinal cord.

Computational functions of neurons and circuits signaling injury: Relationship to pain behavior

The basic circuitry of the “pain pathway” mediating transmission of information from the periphery to the brain is well known, consisting of specialized sensory fibers known as nociceptors projecting to specific spinal cord neurons, which in turn project on to the thalamus and cerebral cortex. Here we survey some of the unique properties of these circuits, such as peripheral and central sensitization, and the segmental and descending modulatory control of synaptic transmission. We also review evidence indicating dissociation between nociceptor activity and behavioral indications of pain. Together, these considerations point to the need for a more quantitative approach to the nociceptive system, specifically the interactions at peripheral, spinal, and supraspinal levels as well as between them, to more fully understand how the activity in nociceptive neurons individually and collectively is related to the pain response.

5.22 – Neurotrophins and Pain

Classical work with neurotrophins, especially with nerve growth factor (NGF) that was the initially discovered neurotrophin, indicated their crucial role as survival factors for sensory neurons during development as embodied in the neurotrophic hypothesis. This, coupled with evidence that they enhanced the growth of neural processes, provided a linchpin for our understanding of neural development, especially of sensory and motor neurons. It has now become apparent that neurotrophins act throughout the life span of the organism and that after birth they take on a different role. NGF is required in the periphery for postnatal differentiation of certain classes of nociceptors. Additionally, NGF acts to increase the sensitivity of nociceptors via an acute action in sensitizing the response to certain stimuli and chronically via upregulation of a number of receptors important in nociceptor function. A different neurotrophin, brain-derived neurotrophic factor (BDNF), upregulated in the soma of tropomyosin-related kinase A-positive (trkA+) sensory neurons during inflammation and released into the spinal cord, acts centrally to sensitize the response of neurons in the superficial dorsal horn to glutamate released by peripheral nociceptors. Recent data indicate that neurotrophins sensitize nociceptive responses in virtually all peripheral tissues. Thus, neurotrophins are widely distributed in different tissues and sensitize many nociceptor functions in their functional action, suggesting that they are poised to contribute to hyperalgesic states. Recent evidence stresses the importance of gaining further understanding of these molecules in order to achieve better insight into how to treat clinical pain states.

Architecture of Sensory Fiber Projections: Implications for Neuronal Specificity in the Spinal Cord

The notion of neuronal specificity implies that a neuron has an identity, conferred, for example, by its surface chemistry, that permits it to contact a defined subset of postsynaptic neurons. Schematic diagrams of connections between regions of the nervous system generally contain an implicit notion of a precise point-to-point projection. Similarly, the concept of a nucleus to which such a neuron might project is generally considered to encompass a compact group of cells.