Molecular mechanisms of peripheral sensitization

Primary afferent neurons are equipped with numerous ion channels and receptors for mediators. Stimuli applied to the sensory endings open ion channels, and the resulting ion currents depolarize the endings. The generation of this receptor potential is called transduction. When the depolarization reaches a certain threshold, voltage-gated ion channels are opened that generate action potentials which are conducted along the axon to the spinal cord. The generation of the action potential is called transformation. Thus, the responsiveness of neurons depends on transduction mechanisms and on the triggering of action potentials.44,45

The elicitation of an action potential by a stimulus is called activation. The previous sections have described changes of mechanosensitivity upon inflammation which are called sensitization (see above under Nociceptors of deep tissue and peripheral sensitization). After sensitiza-tion, action potentials are elicited at lower stimulus energies, and thus a nociceptive neuron may respond to normally innocuous stimuli, in addition to showing an augmented response to noxious stimuli.

Sensitization involves a number of different molecular mechanisms. It results from the effect of numerous inflammatory mediators that bind to receptors in the membrane of the sensory endings, but changes of the intrinsic properties of the neurons also contribute to sensitization. The latter conclusion is derived from findings that dorsal root ganglion or trigeminal neurons from inflamed tissue maintain enhanced excitability even when the neurons are removed from the ganglion and acutely dissociated several days after inflammation of joint46 or muscle.47 In whole cell patch clamp recordings from these neurons, enhanced excitability could be identified by a decrease of the rheobase, an increase in the slope of the stimulus response function assessed with depolarizing current injection, and a decrease in the duration of the action potential after hyperpolarization. Most likely, changes in the activation of voltage-gated K currents i • i 46 47

play an important role. '

As mentioned, nociceptors are equipped with numerous receptors for inflammatory mediators. Binding of mediators to membrane receptors (many of which are coupled to G proteins) activates intracellular second messenger systems. These in turn activate intracellular processes that increase the sensitivity of the ion channels that are involved in stimulus transduction and/or transformation. Mediators are thus able to excite and/or sensitize primary afferent neurons for mechanical and chemical stimuli. These mediators also produce vascular and other changes in the tissue and thus contribute to the inflammatory process itself.

Effects of mediators on joint afferents have been previously summarized in detail elswhere.48 As far as it has been tested, the effects on muscular afferents are comparable. Mediators that have effects on joint afferents include classical inflammatory mediators such as brady-kinin, prostaglandins E2 and I2, and serotonin, purinergic compounds, neuropeptides, cytokines, and others. Common observations are that these mediators (1) affect A8- and/or C-fibers, not Ap-fibers, (2) have an effect only in subpopulations of the units, (3) may or may not affect high threshold, as well as low threshold A8- and C-fibers, and (4) cause some initially mechanoinsensitive afferent fibers to be sensitized and become mechanosensitive.

Bolus injection of bradykinin, an algesic mediator, into joint and muscle arteries may cause an immediate short-lasting activation (less than one minute) of joint and muscle afferents, but thereafter there is a sensitization for mechanical stimuli of joint and muscle afferents that lasts minutes even when bradykinin did not excite the neuron.49'50 Both PGE2 and PGI2 cause ongoing discharges and/or sensitization to mechanical stimulation of the joint. The effect of PGE2 has a slow onset and a duration of minutes, the action of PGI2 begins quickly and has a short duration.51,525354 In addition, these PGs sensitize joint and muscle afferents to the effects of bradykinin whether or not they have an excitatory effect by themselves.42,55 PGE2 and bradykinin together can cause a stronger sensitization to mechanical stimulation than bradykinin or PGE2 alone.49 Conversely, nonsteroidal anti-inflammatory drugs (NSAID), such as aspirin and indometacin, which block PG synthesis, reduce spontaneous discharges from acutely and chronically inflamed joints, and attenuate the responses to mechanical stimu-lation.56,57 Serotonin also sensitizes joint afferents to mechanical stimuli,58,59 and A8- and C-fibers muscle afferents to the action of bradykinin and to excitation by mechanical stimuli.55 Combined i.m. application of bra-dykinin and serotonin causes muscle pain in humans.60

ATP,61, 62 adenosine,62 capsaicin, and anandamide63, 64

excite a proportion of joint afferents (the latter indicate the presence of the TRPV1 receptor). Capsaicin also causes muscle pain in humans.65 Effects have also been observed for neuropeptides. Indeed, substance P66 and VIP67, 68 increased, whereas somatostatin69 and endomorphin70 reduced mechanosensitivity in numerous afferents; the peptides galanin,71 neuropeptide Y,72 and nociceptin73 sensitized some neurons and reduced responses in other neurons. Whether the different patterns of peptide effects (excitation or inhibition) are dependent on the functional state of the neuron is not known at the moment. It was proposed that the simultaneous presence of different neuropeptides regulates excitability of the afferent fibers.

Of particular importance for the progress of arthritis are cytokines such as TNFa, interleukin-1p, and inter-leukin-6. Cytokines play an important role in neuropathic pain,74 but, for example, IL-6 is also able to induce a long-lasting sensitization of C-fibers of the joints to mechanical stimulation.75 Finally, mechanosensitivity can also be influenced by quite different compounds. For example, it was shown that responses of nociceptive articular afferents are reduced by gabapentin,76 a compound used for the treatment of neuropathic pain, and by intra-articular injection of elastoviscous hyaluronan solutions.77

Recordings from afferent fibers from inflamed joints revealed that the proportion of neurons that show an effect of a given mediator can be different from the proportion of responsive afferents from normal joints. This may result from changes of receptor expression. Some data indicate that receptor expression in dorsal root ganglion (DRG) neurons can change in the course of arthritis (e.g. down-regulation of mu-opioid receptors70 or biphasic regulation of somatostatin receptors78). However, changes of the neurons may also result from changes of the milieu in the tissue innervated. Disease processes are dynamic and, therefore, it is likely that different cells and molecules are important at different times in a chronic inflammatory or degenerative process11 or during growth of bone cancer.14 Hence the molecular mechanism of nociception may change over time. This aspect needs much more attention.

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