cholecystokinin and Neuralgia

Recent research on the site of action of morphine, its distribution following systemic administration and activity in a model of neuropathic pain is reviewed. Neuropeptides and pain is discussed in relation to tachykinins and their antagonists, cholecystokinin (CCK) and its antagonists and somatostatin.

Topics: Animals; Cholecystokinin; Endorphins; Humans; Neuralgia; Nociceptors; Pain; Receptors, Adrenergic, alpha; Receptors, Opioid; Sensory Thresholds; Somatostatin; Tachykinins

Current models of somatosensory perception emphasize transmission from primary sensory neurons to the spinal cord and on to the brain

Topics: Animals; Axons; Cholecystokinin; Female; Hindlimb; Hyperalgesia; Interneurons; Male; Mice; Neural Pathways; Neuralgia; Nociception; Pyramidal Tracts; Somatosensory Cortex; Spinal Cord Dorsal Horn; Touch

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

Topics: Action Potentials; Animals; Cholecystokinin; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Inflammation; Neural Pathways; Neuralgia; Neurons; Oxytocin; Paraventricular Hypothalamic Nucleus; Quinoxalines; Rats; Rats, Wistar; Receptors, Oxytocin; Spinal Cord; Supraoptic Nucleus; Transduction, Genetic; Vasopressins; Vesicular Glutamate Transport Protein 2

The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.

Topics: Animals; Area Under Curve; Cholecystokinin; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Formaldehyde; Male; Morphine; Narcotics; Neuralgia; Pain Measurement; Pain Threshold; Peptide Fragments; Proglumide; Rats; Rats, Wistar

It is generally accepted that neuropathic pain is resistant to amelioration by morphine in clinical studies and insensitivity to intrathecal (i.t.) administered morphine in experimental models of neuropathic pain has been demonstrated. This study is to determine if endogenous dynorphin, substance P or cholecystokinin is involved in the lack of anti-allodynia of morphine in a partial sciatic nerve ligation (PSL) model of CD-1 mice. Mice exhibited tactile allodynia in the ipsilateral hind paw 1 day after PSL, and reached its maximal allodynic effect at 2 days and remained allodynic for 7 days. Morphine (3.0 nmol) given i.t. did not alter the tactile allodynic threshold in ipsilateral paw of mice pretreated i.t. with normal rabbit serum 2 days after PSL. However, the same dose of morphine (3.0 nmol) given i.t. reduced markedly allodynia in mice pretreated for 2h with antiserum against dynorphin A(1-17) (200 microg); the morphine-produced anti-allodynia developed slowly, reached its peak effect at 30 min and returned to an allodynic state in 60 min. Similarly, i.t. injection of morphine reduced the allodynia in PSL mice pretreated with antiserum against substance P (10 microg) or cholecystokinin (200 microg) for 2h. Intrathecal pretreatment with antiserum against dynorphin A(1-17), substance P or cholecystokinin for 2h injected alone did not affect the baseline mechanical tactile threshold in ipsilateral paw 2 days after PSL. The results indicate that endogenous dynorphin A(1-17), substance P and cholecystokinin are involved in PSL-induced neuropathic allodynia to attenuate the anti-allodynic effect of morphine.

Topics: Analgesics, Opioid; Animals; Antibodies; Cholecystokinin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Dynorphins; Immune Sera; Injections, Spinal; Ligation; Male; Mice; Morphine; Neuralgia; Peripheral Nervous System Diseases; Sciatic Nerve; Sciatic Neuropathy; Substance P

Neurons in rostral ventromedial medulla and the periaqueductal gray modulate dorsal horn nociceptive transmission. Endogenous peptides implicated in this modulation include enkephalin (ENK), which is antinociceptive, and cholecystokinin (CCK), which has anti-opioid effects. In this study double-label fluorescence immunocytochemistry demonstrated somata and terminals with ENK- or CCK-like immunoreactivity in these regions. Although the distribution of CCK- and ENK-immunoreactive terminal fields overlapped significantly, co-localization was rare. Furthermore, CCK- and ENK-immunoreactive somata had different morphologies and distinct distributions. The overlap of CCK- and ENK- immunoreactive terminals arbors provides a morphological substrate for an antagonistic interaction of CCK and ENK within brainstem pain modulating circuits, as has been demonstrated in the spinal cord.

Topics: Animals; Brain Stem; Cholecystokinin; Enkephalins; Immunohistochemistry; Male; Nerve Endings; Neuralgia; Rats; Rats, Sprague-Dawley