Opioid peptides cause relatively specific inhibition of pain when applied to midline brain structures or when applied directly to the spinal cord. The neural mechanisms which mediate this specific inhibition are only partially understood. While """"""""pain"""""""" can be studied only in humans, """"""""nociception"""""""" (neural responses activated by tissue damaging or potentially tissue damaging stimuli) can be studied in animal models. Nociceptive neural responses are inhibited by opioids paralleling the inhibition of pain. We, therefore, propose to determine whether the specific inhibition of nociception is due to direct, postsynaptic effects on nociceptive neurons in laminae I and II of the spinal cord. To test this, we will record extra- and intracellularly from both nociceptive and non-nociceptive neurons in laminae I and II. We will then apply opioids via micro-iontophoresis and micro-pressure ejection to determine whether they cause conductance changes specifically in the nociceptive neurons. The neurons will be labeled with horseradish peroxidase via the recording micropipette to determine whether cellular morphology contributes to the opioid effects. In other experiments we will determine whether nociceptive neurons in laminae I and II are specifically inhibited when opioid peptides are injected into midline brain structures such as periaqueductal gray. Further experiments are designed to determine the mechanisms of this descending inhibition by using various specific antagonists to block the inhibition at the spinal level. These experiments are designed to determine whether opioid peptides act by producing postsynaptic effects specifically on nociceptive neurons. Future studies could determine which of the various opiate receptor subtypes mediate specific postsynaptic effects, if they are found. The ultimate goal is a better understanding of the mechanism of the opioid blockade of pain with the hope that this understanding will lead to the production of opioids which are more selective, less addicting, and lead to fewer side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004420-05
Application #
3210046
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1987-04-01
Project End
1992-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Vincler, M; Maixner, W; Vierck, C J et al. (2001) Estrous cycle modulation of nociceptive behaviors elicited by electrical stimulation and formalin. Pharmacol Biochem Behav 69:315-24
Schneider, S P; Eckert 3rd, W A; Light, A R (1998) Opioid-activated postsynaptic, inward rectifying potassium currents in whole cell recordings in substantia gelatinosa neurons. J Neurophysiol 80:2954-62
Robinson, G A (1996) Changes in the expression of transcription factors ATF-2 and Fra-2 after axotomy and during regeneration in rat retinal ganglion cells. Brain Res Mol Brain Res 41:57-64
Alvarez, F J; Taylor-Blake, B; Fyffe, R E et al. (1996) Distribution of immunoreactivity for the beta 2 and beta 3 subunits of the GABAA receptor in the mammalian spinal cord. J Comp Neurol 365:392-412
Bove, G M; Light, A R (1995) Calcitonin gene-related peptide and peripherin immunoreactivity in nerve sheaths. Somatosens Mot Res 12:49-57
Robinson, G A (1995) Axotomy-induced regulation of c-Jun expression in regenerating rat retinal ganglion cells. Brain Res Mol Brain Res 30:61-9
Willcockson, H H; Taylor-Blake, B; Light, A R (1995) Induction of fos-like immunoreactivity by electrocutaneous stimulation of the rat hindpaw. Somatosens Mot Res 12:151-61
Bove, G M; Light, A R (1995) Unmyelinated nociceptors of rat paraspinal tissues. J Neurophysiol 73:1752-62
Slugg, R M; Light, A R (1994) Spinal cord and trigeminal projections to the pontine parabrachial region in the rat as demonstrated with Phaseolus vulgaris leucoagglutinin. J Comp Neurol 339:49-61
Light, A R; Sedivec, M J; Casale, E J et al. (1993) Physiological and morphological characteristics of spinal neurons projecting to the parabrachial region of the cat. Somatosens Mot Res 10:309-25

Showing the most recent 10 out of 16 publications