NL-GHK-Cu in pain management and inflammation reduction

NL-GHK-Cu peptide therapy may help restore day-to-day functional comfort by reducing pain and systemic inflammatory processes. In addition, it represents a modern peptide-based approach associated with a marked decrease in the frequency and intensity of the above-mentioned complaints.

Abstract

The mechanisms underlying both pain and inflammation are complex and require appropriate therapeutic management. When treated inadequately, these conditions may lead to numerous burdensome symptoms and clinical consequences. According to available research, the NL-GHK-Cu peptide has potential applications in pain management and in the attenuation of inflammatory responses as a modern peptide therapy.

Keywords: NL-GHK-Cu; pain; acute pain; chronic pain; localized pain; generalized pain; referred pain; multisite pain; inflammation; NL-GHK-Cu therapy

Introduction

By definition, pain is an unpleasant and negative sensory and emotional experience that arises in response to stimuli that damage tissue or pose a threat of tissue damage. Inflammation, in turn, is a defensive response of the body to stimuli that injure its tissues. The purpose of inflammation is to create an environment conducive to repair and regeneration of damaged structures. Both pain and inflammation substantially impair daily life and overall functioning.

The mechanisms of pain and inflammation are complex and necessitate properly targeted therapeutic strategies. If managed inappropriately, these conditions may result in persistent symptoms and multiple adverse consequences. According to research findings, NL-GHK-Cu may be used in pain therapy—among other mechanisms through reducing serotonin release—and in limiting inflammatory activity, including via suppression of pro-inflammatory cytokine production, as a modern peptide-based intervention.

PAIN

Pain, as an unpleasant sensory and emotional experience, is associated with actual, ongoing, or threatened bodily injury. Clinically, pain most commonly arises from stimulation of receptors—specifically nociceptors (pain receptors)—or from a reduced activation threshold of these receptors. The primary role of pain is its protective and warning function: it signals impending tissue injury resulting from trauma or disease and triggers physiological responses aimed at minimizing the consequences of that damage.

Pain enforces limitation of physical activity, which can be beneficial because the associated increase in tissue sensitivity helps prevent further injury. In most cases, initially occurring acute pain resolves—when managed appropriately—within a short period ranging from several hours to several days. In the context of inadequate analgesic management, progressive pathophysiological changes may develop within the central nervous system (CNS), and the initial acute pain state may transition into chronic pain. Therefore, effective intervention at the earliest symptoms is of critical importance.

Pathomechanism of pain

Acute pain

The concept of nociception refers to the process of pain generation, which comprises four stages: transduction, transmission, modulation, and perception. During transduction, the energy of a noxious stimulus (e.g., mechanical, thermal, or chemical) is converted into an electrical impulse conducted by nerve fibres at the peripheral endings of the nociceptor neuron. This process is accompanied by tissue injury and the release of mediators such as bradykinin, serotonin, and substance P, which contribute to neurogenic inflammation at the site of injury, manifesting as pain as well as erythema and oedema.

The encoded information, in the form of an electrical impulse, reaches the dorsal root ganglia of spinal nerves, where excitatory amino acids, substance P, and neurokinin A are released and transported to synapses formed by the central terminals of the nociceptor neuron in the dorsal horn of the spinal cord. From the dorsal horn, nociceptive information is transmitted to higher levels of the CNS. The final stage of nociception is perception in the brain. This stage serves a cognitive function and is responsible for conscious awareness of painful stimulation, its appraisal, and affective and emotional responses. It is also where anxiety, aggression, and anger may arise and where behavioural patterns related to remembered pain are shaped.

Chronic pain

Chronic pain refers to individuals who experience pain over a prolonged period. Clinically, chronic pain symptoms are defined as persisting for more than 3 months or continuing despite healing of the injured tissues. Increasingly, chronic pain is regarded as a disease entity in its own right, requiring specific and specialist therapeutic management. Patients with chronic pain frequently experience symptoms that significantly reduce quality of life, encompassing physiological, psychological, and social disturbances. Symptom severity depends primarily on pain duration and intensity rather than on the initiating cause.

Pain localisation

Localized pain

As the term suggests, localized pain occurs in a single, clearly defined area. Examples include pain confined to a specific abdominal region or toothache.

Referred pain

Referred pain (also termed radiating or transmitted pain) is one of the so-called transferred pains. It most commonly radiates from internal organs to the skin, because each internal organ is associated with a corresponding dermatome. A dermatome is a cutaneous area that receives sensory input via the same spinal nerve as the related organ. Referred pain is often accompanied by contraction (spasm) of the relevant muscle groups. It is not a separate disease entity but rather a symptom of another condition. Referred pain frequently occurs in the cervical, thoracic, and lumbar spine regions. For example, referred pain originating from the cervical spine may suggest conditions such as tonsillitis or peritonsillar abscess.

Generalized pain

This type of pain is most commonly experienced in the context of damage to the somatic nervous system. It is not linked to specific receptors in a single body region; rather, it reflects broader involvement of the nervous system.

Multisite pain

Pain present in ≥4 of 5 body regions, excluding the jaw, chest, and abdomen.

SYSTEMIC INFLAMMATION

Inflammation is a defensive response of the organism to damaging factors. The inflammatory reaction involves immune system cells, connective tissue cells, selected blood proteins, and blood vessels. The objective of inflammation is to limit the harmful factor, neutralize it, and repair damaged tissues.

Course of the inflammatory response

Warming, redness, and swelling of the inflamed area are direct consequences of the vascular response to tissue injury. Initially, there is a rapid, short-lived vasoconstriction, followed by prolonged vasodilation. Simultaneously, capillary endothelial permeability increases, causing fluid to move into the extravascular space and resulting in oedema. Subsequently, immune cells migrate to the site of tissue injury, forming an inflammatory infiltrate. Neutrophils are the first cells to appear at the inflammatory focus, followed by eosinophils (in allergic reactions) and lymphocytes and macrophages (particularly in chronic inflammatory responses). Leukocyte migration from the intravascular space is mediated by the presence of adhesion molecules on the surface of endothelial cells and leukocytes.

Analgesic activity of NL-GHK-Cu

Experimental studies have demonstrated that NL-GHK-Cu exhibits analgesic activity. In particular, the peptide component L-lysine is considered to play a key role in the analgesic process. Through its action, the peptide regulates and triggers peptidase activity and contributes to the formation of tissue-specific processing products. It has also been shown that NL-GHK-Cu reduces serotonin secretion, which is implicated in the development of neurogenic inflammation at the site of injury or tissue damage, thereby contributing to pain-related symptoms.

Anti-inflammatory activity of NL-GHK-Cu

It has been shown that the NL-GHK-Cu complex supports inhibition of inflammatory and fibrotic changes and attenuates the inflammatory response by reducing levels of pro-inflammatory cytokines TNF-α and IL-6, as well as MPO activity (myeloperoxidase concentration). Moreover, NL-GHK-Cu significantly reverses the MMP-9/TIMP-1 imbalance and partially prevents EMT (epithelial–mesenchymal transition) via modulation of the Nrf2, NF-κB, and TGFβ1 pathways, as well as Smad2/3 phosphorylation.

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