Enkephalinergic

Enkephalinergic refers to neural systems and signaling that use enkephalins, a class of endogenous opioid peptides, as their transmitter or modulator. Enkephalins are short peptides produced from the larger precursor proenkephalin (PENK). The primary enkephalins are met-enkephalin and leu-enkephalin, typically generated by proteolytic processing of PENK in various brain regions and the spinal cord.

Pharmacology and receptors: Enkephalins preferentially bind delta opioid receptors, with lower affinity for mu receptors and limited activity at kappa receptors. Activation of these receptors inhibits neuronal excitability and neurotransmitter release, contributing to analgesia and emotional regulation. In the CNS and peripheral nervous system, enkephalin signaling modulates pain transmission, mood, and reward pathways. Enkephalins are rapidly degraded by enkephalinases, such as neutral endopeptidase and aminopeptidases, which shortens their signaling duration and complicates pharmacologic manipulation.

Distribution and function: Enkephalinergic neurons are found in several brain regions involved in pain and emotion, including the dorsal horn of the spinal cord, periaqueductal gray, amygdala, nucleus accumbens, and other parts of the striatum, as well as certain hypothalamic nuclei. In the spinal cord, enkephalinergic interneurons can inhibit excitatory nociceptive inputs, contributing to both spinal and supraspinal analgesia. Beyond pain, enkephalinergic signaling participates in stress responses, feeding, and reinforcement processes.

Clinical relevance: Because enkephalins produce analgesia with a relatively restricted receptor profile, there is interest in therapies that boost enkephalin signaling (for example, by inhibiting enkephalin degradation) as potential pain treatments with distinct safety profiles. Enkephalinergic pathways also intersect with mechanisms of opioid tolerance and dependence.