Antidromic Impulses

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An example contrasting orthodromic and antidromic effects is seen in Riot Control Agents (tear gas). Chemicals such as capsaicin (OC) activate the TRPV1 channel causing an influx of Na and Ca ions generating a pain signal to the brain via orthodromic pathways. The nerve impulse also travels backward to adjacent nerve endings (antidromic stimulation, via axon reflex mechanism), causing them to release inflammatory neuropeptides Substance P and CGRP. This secondary release enhances the inflammatory response, leading to the characteristic symptoms of tear gas exposure.
CGRP, Calcitonin-Gene Related Peptide; CN, chloroacetophenone; CR, Dibenzoxazepine; CS, chlorobenzylidene malononitrile; TRPA1, Transient Receptor Potential Ankyrin 1; TRPV1, Transient Receptor Potential Vanilloid 1.

Antidromic impulses means action potentials that are conducted in the opposite to normal (orthodromic) direction. The most clinically relevant example is sensory neurons, where they conduct efferent instead of the usual afferent impulses. This can result in the release of substance P and CGRP with resultant neuroinflammation. These substances are inflammatory on their own but also recruit mast cells and their subsequent release of histamine, cytokines, and other molecules that augment vasodilation.

Orthodromic vs Antidromic Conduction

Orthodromic conduction

See also: Nociception, Sensory Physiology

Orthodromic conduction refers to action potentials traveling in the functionally “forward” direction along a neuron. For example, in a primary sensory neuron (a pseudounipolar cell in the dorsal root ganglion, DRG), orthodromic impulses originate in the peripheral nerve ending (e.g. skin, disc, facet joint) and propagate toward the DRG and then into the spinal dorsal horn. The function is to drive synaptic transmission in the dorsal horn, leading to pain perception or reflexes.

Antidromic conduction

By contrast, antidromic conduction is the propagation of impulses backward along the neuron – from central toward peripheral terminals in sensory fibers, or from axon terminals toward the cell body in other neuron types. Anatomically, the pseudounipolar structure of DRG neurons (with a T-shaped axon bifurcation into central and peripheral branches) allows action potentials to theoretically propagate in either direction. Under normal circumstances, orthodromic transmission predominates, carrying sensory information to the central nervous system. However, when triggered by certain stimuli or pathological conditions, antidromic impulses can occur. Notably, even large myelinated fibers and unmyelinated C-fibers are capable of conducting antidromically.

Andidromic firing is described as a form of "efferent" activity of sensory neurons. It turns the sensory fibre into an effector, mediating responses like vasodilation, plasma extravasation, and modulation of local immune cells. This phenomenon underlies axon reflexes and dorsal root reflexes, which are distinct but related antidromic mechanisms.

Antidromic conduction does not convey conscious sensation; instead, it induces peripheral tissue changes that can indirectly influence pain. For example, antidromic activity in nociceptive fibers causes release of substance P (SP), calcitonin gene-related peptide (CGRP), and other neuropeptides from the peripheral endings. These agents promote vasodilation and inflammatory oedema, sensitizing nociceptors and setting the stage for pain amplification. Thus, while orthodromic signaling is the “input” for pain, antidromic signaling creates a “feedback loop” that can exacerbate or perpetuate pain via neurogenic inflammation.

It helps explain why patients with nerve injury or inflammation may exhibit neurogenic flare (reddening or swelling in the affected dermatome) and why treating pain isn’t only about blocking ascending signals but also breaking local inflammatory cycles. In nerve conduction studies, the concept of antidromic vs. orthodromic stimulation is used intentionally (e.g. stimulating a sensory nerve distally and recording proximally is orthodromic; the reverse is antidromic).

Dorsal root reflexes are centrally triggered antidromic discharges that cause peripheral neurogenic inflammation, whereas axon reflexes are peripherally contained antidromic spreads within a branching nerve. Both result in the release of inflammatory neuropeptides and both amplify pain by increasing peripheral sensitisation. Together, they constitute the afferent neuron’s “efferent” functions.

Origins of Antidromic Activity

While antidromic activity has long been associated with axon reflexes in the skin and dorsal root reflexes in the spinal cord, modern research provides a more complete picture. The work of Sorkin et al synthesizes evidence for five distinct anatomical points of origin where antidromic action potentials can be generated. These impulses travel away from the spinal cord to cause the peripheral release of neuropeptides (particularly substance P and CGRP), driving neurogenic inflammation. The sensory neurons can also release anti-inflammatory neuropeptides such as somatostatin and galanin. The system has both accelerators and brakes. These five mechanisms are described below in order from peripheral to central.

Antidromic impulses and their manifestations (dorsal root reflexes, axon reflexes, neurogenic inflammation) show that sensory neurons are active participants in modulating their own environment.

Peripheral Afferent Collaterals (Axon Reflexes)

Axon reflexes, on the other hand, are a more peripheral phenomenon often discussed in the context of cutaneous neurogenic inflammation. In an axon reflex, a single afferent neuron with branching terminals can propagate an impulse from one branch to another without involving the spinal cord. For instance, if a peripheral nerve fibre is stimulated at one of its branches (say by a cut or by capsaicin), the impulse can travel antidromically to the branch point and then orthodromically into a neighboring branch, causing release of SP and CGRP in adjacent skin territory. This produces the “flare” response around a site of injury. The axon reflex is essentially a local reflex within the nerve’s arborization, requiring no synapse or central mediation – the neuron stimulates itself in neighboring areas. In the skin, this explains why a localized insult leads to a halo of reddening and heightened sensitivity around the wound.

While axon reflexes are classically described in the skin (triple response of Lewis), similar principles apply in deep tissues innervated by branching nociceptors. The classic ‘flare’ reflects both neuropeptide actions and interaction with mast cells. Mast cells act as downstream amplifiers of this signal rather than generators of the initial antidromic impulse. SP/CGRP released from antidromically activated endings can directly trigger mast-cell degranulation via the MRGPRX2 receptor, while histamine then feeds back on H1/H4 receptors to sensitize TRPV1/TRPA1 on nociceptors. This specific neuron-mast-cell interaction is relevant in the neurogenic flare of the skin, visceral hypersensitivity, and the dural inflammation of migraine.

In the spine, a single DRG neuron may send branches to multiple structures (e.g. disc and sinuvertebral nerve branches, or multifidus muscle and skin). An impulse triggered in one branch (perhaps by discogenic pain) could reflexively cause mediator release in another branch’s target (perhaps in paraspinal musculature), contributing to muscle tenderness or spasm. Moreover, axon reflexes in nerve root afferents could produce vasomotor changes in the distribution of the nerve. For example, patients with sciatica sometimes exhibit erythema or swelling in the leg; while sympathetic changes can be involved, a component of this may be axon reflex release of neuropeptides from the sciatic nerve’s cutaneous branches.

Single DRG neurons have been shown to innervate both the colon and the urinary bladder, or both lumbar facet joints and the sciatic nerve. This explains how irritation in one organ can lead to neurogenic inflammation and sensitivity in a completely separate structure. See Visceral Pain.

Proximal Afferent Collaterals

Significant branching of sensory axons occurs very close to the DRG, particularly for unmyelinated fibers. This creates another level where antidromic activity can spread between different nerve branches before they travel to the periphery.

Electron microscopy studies reveal a significant increase in the number of axons just distal to the DRG compared to the number of neurons within it, with one study finding a ratio of 2.3 axons per neuron in the sacral segments of the rat. This demonstrates that substantial branching occurs proximally, especially in unmyelinated fibers.

Mid-Axonal Activation

The axon itself can become a source of antidromic signals, especially in an inflammatory environment. This can happen through ephaptic transmission and chemical irritation.

Ephaptic Transmission ("Crosstalk"): In bundles of unmyelinated C-fibres (Remak bundles), axons are not perfectly insulated. Activity in one fiber can trigger bidirectional action potentials in an adjacent fiber due to the imperfect insulation.

Chemical/Thermal Irritation: Pro-inflammatory mediators like tumor necrosis factor (TNF), ATP, and serotonin can directly activate receptors (like TRPV1) located on the axon membrane, generating action potentials mid-way along the nerve that travel in both directions. In an inflammatory site, factors like increased temperature and acidity can work synergistically to activate channels like TRPV1 on the axon, further contributing to the generation of ectopic activity.

The Doral Root Ganglion

After injury or inflammation, the dorsal root ganglion (DRG) itself can become an ectopic "pacemaker," spontaneously generating action potentials that travel both centrally and peripherally. This hyperexcitability is driven by several concurrent changes:

Ion channels: The neuronal membrane becomes more excitable due to an increased expression of excitatory sodium (NaV) and calcium (VGCC) channels, alongside a decreased expression of inhibitory potassium (K+) channels.

Immune changes: After injury, satellite glial cells surrounding the DRG neurons increase their communication with the neurons through gap junctions. These activated satellite cells can release substances like TNF that excite the DRG neurons. Macrophages and T-lymphocytes can migrate into the DRG and release a variety of pro-inflammatory cytokines that increase neuronal activity.

Nerve fibre sprouting: Nerve fibers sprout within the ganglion to form "baskets" around neuronal cell bodies. These can be sympathetic fibers, which make the neurons sensitive to norepinephrine, or collaterals from other peptidergic (CGRP-containing) sensory neurons.

• Sympathetic Fibers: Post-ganglionic sympathetic terminals can form basket-like structures around DRG neurons, making them sensitive to norepinephrine.
• Peptidergic Afferents: CGRP-containing sensory neurons can also sprout and form collaterals that wrap around other DRG neurons.

Dorsal Root Reflexes (Spinal Dorsal Horn)

Dorsal root reflexes (DRRs) are an example of antidromic impulses in the spinal cord. A DRR is essentially a reflexive discharge that originates within the dorsal horn circuitry and travels out backwards through the dorsal root along primary afferent fibers.

In this process, the sensory neuron functions like a motor neuron: it releases neurotransmitters from its peripheral terminals rather than just sending signals to the CNS. DRRs were first described in the early 20th century and later studied in detail by Wall, Willis, and others. The classical mechanism involves a series of synaptic events:

• Intense activation of nociceptive afferents (e.g. by tissue injury, inflammation, or even electrical stimulation) causes excessive glutamate release in the superficial dorsal horn. This glutamatergic drive activates interneurons, including excitatory interneurons and GABAergic inhibitory interneurons.
• Normally, GABAergic interneurons mediate presynaptic inhibition of primary afferents via GABA-A receptors on the central terminals of those afferents. This causes primary afferent depolarization (PAD) which decreases transmitter release (a gating mechanism to modulate input). However, if the stimulus is strong enough, PAD can become so large that it triggers the afferent to fire an action potential antidromically. In other words, the mechanism intended to inhibit the afferent (GABA-mediated depolarization) paradoxically causes it to fire backwards – converting an inhibitory process into an excitatory one. This is the genesis of a dorsal root reflex.
• The DRR propagates out the dorsal root in both myelinated Aδ fibers and unmyelinated C-fibers, and it can be observed as compound action potentials leaving the cord. Importantly, these antidromic discharges can be abolished by blocking GABA-A receptors (e.g. with bicuculline) in the spinal cord, underscoring the role of the GABAergic PAD mechanism in their origin. Note, while capsaicin-induced DRRs are conveyed by Aδ and C-fibers, inflammation from arthritis can induce DRRs in larger myelinated Group II fibers as well.
• When the antidromic spike reaches the peripheral endings of the afferent neuron, it causes the release of neuropeptides and other mediators stored in those terminals. Notably, substance P (SP), CGRP, and other neuropeptides (neurokinins, etc.) are released from sensory endings during DRRs. SP acts on neurokinin receptors to increase vascular permeability, leading to plasma extravasation (tissue edema), while CGRP causes arteriolar vasodilation. Together, these produce the classic signs of neurogenic inflammation: redness (flare), warmth, and swelling in the affected tissue. These substances also sensitize nearby pain receptors and recruit “silent” nociceptors (previously inactive fibers that begin firing when inflamed.
• The result is a vicious cycle: the neurogenic inflammation feeds back to activate more nociceptive afferents (orthodromically this time), which sustain central excitation, which can in turn trigger more DRRs. Sluka et al. described this as a “vicious cycle” of pain and inflammation – a positive feedback loop that can lead to persistent pain and hyperalgesia if not interrupted. In acute injuries, this cycle may subside as inflammation resolves, but in chronic pain, DRRs can act as initiators or perpetuators of ongoing pain. Indeed, DRRs are thought to provide a neurogenic amplification loop that maintains both peripheral inflammation and central sensitization in chronic pain states. As one review succinctly stated, “the dorsal root reflex is an important mechanism for the neurogenic amplification loop and the persistence of both inflammation and enhanced hyperalgesic nociception".
• The antidromic spikes generated by DRRs also engage mast cells (via the MRGPRX2 receptor); SP/CGRP-evoked degranulation supplies histamine and proteases that further increase vascular permeability and sustain the neurogenic flare.

DRRs are not only triggered by intense peripheral pain signals. They can also be initiated by descending pathways from the brainstem. For example, serotonergic (5-HT) neurons can act on receptors on the primary afferent terminals, triggering DRRs independently of peripheral input. This directly links central pain modulation systems to the generation of peripheral neurogenic inflammation.

A unilateral injury can trigger DRRs bilaterally. This is a potential explanation for the clinical phenomenon of "mirror-image pain," where inflammation and sensitivity develop on the contralateral side of an injury.

From a clinical perspective, dorsal root reflexes offer an explanation for why an injury can lead not only to local pain but also to spread of pain and inflammation beyond the initial site. For example, after a joint injury, patients often experience flare and increased sensitivity in surrounding tissues; DRRs and the resulting neurogenic inflammation can account for that spread. In spinal pain, DRRs imply that the central nervous system (dorsal horn) can actively drive peripheral pathology, not just receive it. This blurs the line between “nociceptive” pain (driven by tissue injury) and “neuropathic” pain (driven by nerve dysfunction), since a neuropathic process in the dorsal horn (disinhibition and DRRs) produces nociceptor activation in the periphery.

Specific Conditions

Antidromic activity is recognised as a contributor to certain chronic pain problems. They create feedback loops between the dorsal horn and peripheral tissues. They help explain the “neurogenic flare” and persistent inflammation seen in many chronic pain conditions. Key examples are below:

Migraine

Main article: Migraine

Migraine headache is a primary example of a clinical condition where antidromic vasodilation is considered a key mechanism. The underlying process is a form of neurogenic inflammation originating from the trigeminal nerves that innervate cranial blood vessels. During a migraine, these sensory nerves are activated, leading to the antidromic release of neuropeptides, most notably Calcitonin Gene-Related Peptide (CGRP), from their peripheral terminals onto the arterial smooth muscle. While Substance P is a key mediator of neurogenic inflammation in rodents, its role in humans is considered minimal; CGRP is recognized as the principal vasodilator. This release of CGRP causes significant dilation of intra- and extracranial arteries, such as the middle meningeal artery, which is strongly associated with the onset and lateralization of throbbing migraine pain. This link is confirmed by findings that CGRP levels are elevated in cranial blood during attacks and that CGRP receptor antagonists are highly effective at aborting migraine headaches. Dural mast cells sit in tight apposition to trigeminal afferents; CGRP and SP can degranulate them, and the released histamine/cytokines amplify meningeal vasodilation and nociceptor sensitization.

This pathway also explains how various environmental factors can trigger migraine attacks. Many triggers, such as ethanol, acrolein (found in cigarette smoke), and umbellulone (from the "headache tree"), are agonists or sensitisers of TRP ion channels (specifically TRPV1 and TRPA1) located on the sensory nerve endings. Stimulation of these channels provides the initial stimulus for the antidromic impulse, initiating the CGRP release and subsequent vasodilation that leads to pain. Treatments like triptans (e.g., sumatriptan) intervene in this process through a dual mechanism: they directly cause vasoconstriction of the dilated arteries and also act on presynaptic 5-HT₁D receptors on the nerve terminals to inhibit further antidromic release of CGRP.

CRPS

Main article: CRPS

Part of the pathophysiology of CRPS involves neurogenic inflammation and can at least partially explain some of the clinical features such as vasodilation, oedema, and sudomotor changes. In CRPS, peripheral nociceptive C-fibres are stimulated, and this leads to both orthodromic (afferent) flow to the DRG as well as antidromic (efferent) flow to the affected tissue. This efferent transmission results in the release of substance P and CGRP; as well as other compounds such as VIP, neurokinin B, adrenomedullin, neuropeptide Y and gastrin-releasing peptide. This leads to the promotion of further inflammation. Serum levels of CGRP have been found to be significantly elevated in CRPS patients compared to controls. The same study however found that pain and hyperalgesia, particularly in the chronic stages, were independent of CGRP levels.

Neurogenic inflammation is only one contributor to the pathophysiology, central sympathetic dysregulation is another. Early, warm-phase CRPS I often shows a central loss of cutaneous sympathetic vasoconstrictor reflexes with subsequent recovery as symptoms settle. This pattern supports a central autonomic component alongside peripheral neurogenic inflammation.

Discogenic and Facet Joint Pain

Main article: Chronic Low Back Pain

The intervertebral discs and facet joints are innervated by sensory fibers that can release neuropeptides when stimulated antidromically. This “neurogenic inflammation” may aggravate degeneration and pain.

In a recent animal study, injury to a lumbar disc triggered upregulation of SP, CGRP, and inflammatory cytokines not only in the injured disc but also in adjacent discs, presumably via antidromic spread through multisegmental innervation. Within 24 hours, both the injured and neighboring discs showed elevated pro-inflammatory mediators, an effect that was blunted by an NGF (nerve growth factor) receptor antagonist. These findings suggest that one painful disc can induce a cascade of neurogenic inflammation in the spinal column, potentially contributing to progressive disc degeneration and chronic low back.

Similarly, facet joint inflammation (as in osteoarthritis) is associated with increased SP in joint tissues, indicating local neuropeptide release that can sensitize nociceptors. Antidromic impulses in the medial branch nerves could theoretically sustain inflammation in facet joints analogous to how they do in arthritic knees.

Radicular Pain

Main article: Radicular Pain and Radiculopathy

Lumbar or cervical radiculopathy often involves a combination of mechanical compression and chemical irritation of a spinal nerve root. Beyond compression by a herniated disc, the dorsal root or DRG may become inflamed due to nucleus pulposus leakage and cytokine release.

Radicular pain is a multifactorial pain syndrome involving ischemic, inflammatory, mechanical, and neuropathic components. Chemical mediators like IL-1, IL-6, TNF-α, and SP have been found around compressed roots. These inflammatory agents can both stimulate orthodromic nociceptive firing and be released in part via antidromic activation, creating a vicious cycle of inflammation and pain.

Orthodromic impulses cause the radiating limb pain and paresthesias. Antidromic impulses in an irritated nerve root can cause the root’s distal endings (and collateral branches) to release neuropeptides, leading to swelling of the root sheath (radiculitis) and worsening pain. Nerve root swelling can sometimes be seen on MRI, and also intraoperatively correlating with SP and CGRP release locally.

Patients with radicular pain often describe burning, lancinating pain – a quality suggestive of ectopic nerve firing. It is likely that spontaneously active DRG neurons send impulses both centrally (causing radiating pain) and peripherally (causing neurogenic inflammation in skin or muscle). This may explain phenomena like tactile allodynia or warmth in the affected region.

Transforaminal epidural steroid injections could potentially dampen both orthodromic and antidromic signaling.

Neuropathic Pain and Ectopic Discharges

Main article: Neuropathic Pain

Neuropathic pain (from nerve injury, diabetic neuropathy, etc.) is characterized by hyperexcitable neurons that fire without normal provocation. These ectopic discharges often originate in the DRG or along the nerve. Such firing can travel orthodromically (perceived as tingling, pain, or electric shocks) and antidromically.

Antidromic spikes cause the peripheral release of SP, CGRP, and other transmitters, which in turn produce redness, edema, or trophic changes (as seen, for example, in complex regional pain syndrome where limbs may become warm, swollen, and sweaty due to neurogenic inflammation).

In neuropathic conditions, dorsal horn disinhibition (loss of inhibitory interneuron function) may allow even large low-threshold fibers to trigger pain pathways. For instance, Aβ touch fibers, normally unrelated to pain, can gain access to pain-transmission neurons in lamina I of the dorsal horn when inhibition is impaired. These same dorsal horn circuit changes facilitate antidromic activity: a disinhibited dorsal horn more readily generates dorsal root reflexes (discussed below) that send impulses out the dorsal roots.

Nociplastic pain

Main article: Nociplastic Pain

Chronic pain often leads to central sensitization, wherein the spinal cord dorsal horn neurons become hyper-responsive and fire excessively to a given input. In such states, even subthreshold or normally innocuous inputs can produce pain (allodynia), and pain outlasts the stimulus.

Central sensitisation is partly driven by persistent C-fibre input, but it also has a reflexive component: the hyperexcitable dorsal horn can generate dorsal root reflexes (DRRs) spontaneously. Animal studies have recorded spontaneous antidromic discharges (sometimes called “spontaneous DRRs”) in dorsal roots during central sensitization, representing synchronous firing of primary afferents initiated within the cord. These antidromic spikes perpetuate peripheral neurogenic inflammation, keeping tissues inflamed and nociceptors sensitized even in the absence of ongoing injury.

Thus, central sensitization is not purely a central phenomenon – it has a reverberating peripheral dimension via antidromic impulses. Clinically, patients with centrally sensitised pain (e.g. fibromyalgia, chronic widespread pain) may have features like diffuse hyperalgesia or swelling that suggest a neurogenic inflammatory component. People with fibromyalgia have evidence of diminished spinal inhibition (disinhibition), which could lower the threshold for DRR generation. This underscores the need to treat not only the “brain” aspects of central sensitisation but also the spinal cord neurochemical milieu that allows these self-sustaining pain loops.

Therapeutic Implications

If antidromic impulses and the resultant neurogenic inflammation contribute to pain perpetuation, then this aspect of nociception may be a reasonable target.

Inverventional Approaches

• Nerve blocks and epidural injections: These will silence both orthodromic and antidromic traffic
• Thermal ablation: Ablation of the small sensory afferents removes their ability to conduct impulses in either direction.
• Pulsed radiofrequency DRG ablation: Reduction in ectopic firing.
• Neuromodulation (Spinal Cord Stimulation and DRG Stimulation): Modulates dorsal horn activity by activating large Aβ fibers and engaging both segmental and descending inhibitory pathways. Reduction in hyperexcitability and therefore potentially less DRRs.
• Dorsal Root Ganglion Stimulation (DRG-S): stabilises DRG neurons to prevent ectopic firing and abnormal sensory transmission, with less paresthesia than spinal cord stimulation.

Pharmacotherapy

• CGRP Pathway Blockade: Best known as a migraine target. But CGRP is also involved in spine pain mechanisms, and research is needed to see if there is a role for spine pain and other pain conditions. CGRP is upregulated in degenerative disc disease and spondylosis, where it can stimulate release of cytokines like TNF-α, IL-6, and NGF, and sensitize nociceptors. An observational study examined patients with coexisting degenerative spinal pain and migraines who started on anti-CGRP migraine therapy. The results showed a significant off-target reduction in back and neck pain after patients began CGRP inhibitor treatment from 6.30 to 4.36 on average. P
• NGF Inhibitors: Nerve Growth Factor is another molecule that mediates pain and inflammation; it sensitizes primary afferents and fosters sprouting of nociceptive fibers. Unfortunately there were adverse effects on joint integrity in humans but not animals, and so development has slowed.
• Membrane-Stabilizing Agents: Drugs like gabapentinoids (gabapentin, pregabalin) and certain antiarrhythmics or sodium channel blockers (e.g. mexiletine) reduce the frequency and intensity of ectopic discharges from injured nerves. By binding to the α2δ subunit of voltage-gated calcium channels, gabapentinoids decrease excitatory transmitter release in the dorsal horn and likely reduce the overall firing of DRG neurons. Studies specifically on gabapentin and DRRs are mixed, it does not appear to directly suppress dorsal root reflex potentials in all models. Topical lidocaine or systemic sodium channel blockers can diminish spontaneous firing in peripheral nerves, indirectly curbing antidromic activity.
• GABA Agonists and Glycine Agonists: Since dorsal root reflexes hinge on GABA-A activity, one might think GABA agonists would exacerbate DRRs (as high doses could further depolarize afferents). In practice, systemic GABAergic drugs (benzodiazepines, baclofen (GABA-B agonist) are not primary analgesics for nociceptive pain, though baclofen can help neuropathic pain by reducing excitability of spinal networks.
• Capsaicin: A TRPV1 agonist, initially causes massive release of SP/CGRP (a burst of antidromic-like activity), but then leads to long-lasting desensitization and even degeneration of the nociceptor terminals. High-concentration capsaicin patches (8% Qutenza) are used for peripheral neuropathic pain (like post-herpetic neuralgia) to reduce local nerve sensitization but are difficult to source in New Zealand.
• Anti-glial and Cytokine Therapies: Therapies that reduce spinal glial activation (minocycline, ibudilast) or neutralize pro-inflammatory cytokines (like anti-TNF agents) might attenuate the central amplification that leads to DRRs. Some small studies with chronic pain patients (e.g. sciatica with elevated TNF in disc herniation) have explored local anti-TNF injection with mixed results.
• Mast Cell Stabilisers: Sodium cromoglycate may reduce some of the downstream effects related to mast cell degranulation.

Physical and Rehabilitation Strategies

Physical therapy and related modalities also influence antidromic activity. Exercise has systemic anti-inflammatory effects – regular aerobic exercise is known to reduce levels of inflammatory cytokines and can increase endorphins, which may raise pain thresholds. Movement also stimulates large diameter mechanoreceptors (Aβ fibers), helping to close the “gate” at the spinal cord and potentially suppressing the interneuronal activity that leads to DRRs.

Manual therapies (massage, chiropractic adjustments) and acupuncture may transiently modulate nerve activity and improve local blood flow, flushing out inflammatory mediators. Transcutaneous electrical nerve stimulation (TENS), mentioned earlier, drives Aβ fiber activity and segmental inhibition, which might reduce neurogenic inflammation by preventing pain-facilitating reflex arcs.

There is also a role for patient education and pacing – by avoiding constant pain provocation and practicing paced activity, patients give their nervous system fewer opportunities to engage in runaway feedback loops. In centrally sensitized patients, techniques like mindfulness or cognitive behavioral therapy can down-regulate overall sympathetic and glial activation, indirectly mitigating some pain-amplifying pathways. While these non-invasive approaches don’t target antidromic impulses as specifically as an injection or drug might, they contribute to a holistic reduction in the “gain” of the nervous system that favors relief over perpetuation of pain.

Further Reading

Antidromic vasodilatation and the migraine mechanism - Geppetti 2012.pdf- 233 KB (f)

Antidromic activity neurogenic inflammation - Sorkin 2018.pdf- 1.01 MB (f)