[4] Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord.
[9] Dynorphin is produced in many different parts of the nervous system, including the hypothalamus, the striatum, the hippocampus and the spinal cord.
Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency.
[12] The authors found that administration of truncated dynorphin A2-17, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in microglia in the dorsal horn of the spinal cord.
Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain.
[14] This same group also showed that the dynorphin-KOR system mediates astrocyte proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses.
[15] Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.
[17] One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by CREB (3’, 5’-monophosphate response element binding protein).
According to the model proposed by Carlezon et al., use of cocaine increases the expression of cAMP and cAMP-dependent protein kinase (PKA).
[18] PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction.
Northern blot analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.
[21] Land et al. first described a mechanism of dysphoria in which corticotropin-releasing factor (CRF) provokes dynorphin release.
[22] Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR.
[24][25] A downstream element of this pathway was later identified by Bruchas et al.[26] The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation.
Newton et al.[27] studied the effects of CREB and dynorphin on learned helplessness (an animal model for depression) in mice.
[27] As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes.
The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness.
First, increased dynorphin levels block the release of glutamate, a neurotransmitter involved in plasticity in the hippocampus, which would inhibit new learning.
[28] Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness.
[38] Mandenoff et al.[32] proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions.
Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.
Opioid peptides were first investigated in hyperthermia, where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain.
[3] Xin et al.[39] showed that delivery of dynorphin A1-17 (a KOR agonist) through microdialysis into the PAG region induced hypothermia in rats.
Sharma and Alm[40] found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem.
Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress.
Sharma and Alm[40] concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction.