# Presentation: 179430

**Nicotine-Opioid System Interactions: ****From Mouse to Man to Medicine**
** **
**PENN TTURC          Abramson Cancer Center**

## Nicotine Dependence Treatment

**Despite progress in tobacco control research, almost one quarter of Americans continue to smoke.**

**There is a need to develop new treatment models that can be readily translated to the clinical setting to maximize the effectiveness of nicotine dependence treatment.**

**FDA-approved medications, NRT and bupropion, are effective for only a fraction of smokers. As many as 80% of smokers respond poorly or not at all to these therapies. **

## TTURC2 ResearchMission Statement

- To translate discoveries in basic neuroscience, pharmacology, genetics, and behavioral science to improve treatment for nicotine dependence.

## Pharmacogenetic Model of Nicotine Dependence Treatment

_**Genetic Pathways**_
**Opioid **
**Dopamine **
**Norepinephrine**
**Glutamate**

_**Outcomes**_
**Abstinence**
**Relapse Curves**

_**Intermediate Markers **_
**Nicotine reward**
**Abstinence effects**
**    ****Psychological**
**    ****Hormonal**
**    ****Neurocognitive**

## From the Laboratory to the Clinic:            Nicotine-Opioid Interactions

## Conditioned Place Preference

- Preconditioning Day

- Test Day

-  A                B

-  A                B

-  A                B

-  A                B

- C

- C

- S

- S

- S

**??**

**Test Day**

***Work in Julie Blendy’s lab***

**Conditioning phase (Days 2-8)**

**Pre-conditioning day: roam free**

**nicotine**

**saline**

## Naloxone on Test Day Blocks Conditioned Rewarding Effects of Nicotine in 129/C57 B16 Mice 

- Saline

- Nicotine (1.0mg/kg)

- Treatment on Test Day

- *p<.05

- *

- Time on paired minus time on unpaired

***Walters et al, ***_***Neuron***_***, 2005***

- Nicotine (2.0mg/kg)

- Nicotine on Pairing Days

## Nicotine Choice Paradigm*

**Smoke own brand cigarette following arrival to the clinic**
**2 hour deprivation period (to standardize exposure without inducing serious withdrawal symptoms)**
**Initial (blinded) exposure to 4 puffs of Quest cigarettes: denic. (.05 mg) vs nic. (.6 mg) with 30-minute interval. Assess subjective effects**
** ****Self-administer 4 puffs from either cigarette at 30 minute intervals over a 2-hour period **
**Standardized puffing procedure – no differences in smoking topography**
**Outcome measure is number of nicotine puffs chosen out of 16 = relative reinforcing value of nicotine**

**Paradigm validated by Ken Perkins (1996, 1999, 2002). # nicotine choices sensitive to differences in deprivation and predicts abstinence*

## Effects of Naltrexone Single Acute Dose 50mg on the Relative Reinforcing Value of Nicotine:

**Mean # of nicotine puffs**

**Within Subject Mixed Effects Model (p=.03)**

***Rukstalis et al, Psychopharm, 2005***

- 71%  of puffs nicotine

- 60%  of puffs nicotine

## The Human OPRM1 Gene

**   **

**PROMOTOR       EXON 1    EXON 2   EXON 3        EXON 4  3’UTR**

**A118G**

**The human OPRM1 gene includes a common Exon 1 Asn40Asp (A118G) mis-sense single nucleotide polymorphism (SNP).  **
**G allele associated with reduced mRNA expression and protein levels (Zhang et al., 2005) and is present in 25-30% of persons of European ancestry. **
**Hypothesis: Smokers with G allele will have a lower liability to relapse in smoking cessation treatment **

## Open Label Trial of Nicotine Patch vs. Nicotine Nasal Spray  (n=600)

- Orientation & Screening

- NS + 7 sessions group counseling

- TN+ 7 sessions group counseling

- Follow-Up: EOT, 6-months, and 12-months

- Pre-treatment Assessment & Genotyping

- 95% retention rate

## OPRM1 Asn40Asp Variant is Associated with Response to Nicotine Replacement Therapy 

**OPRM1 Asn40Asp Variant is Associated with Response to Nicotine Replacement Therapy **

- Treatment Phase

- Follow-up Phase

- CO-verified abstinence

***Lerman et al., ***_***Pharmacogenomics J***_***, 2004***

## Smokers with Asp40 Variant Report Greater Reductions in Negative Affect During NRT

- quit

- Negative Affect (PANAS)

**p=<.001 in linear regression model**

***Lerman et al., ***_***Pharmacogenomics J***_***, 2004***

## Smokers with Asp40 Variant Gain Less Weight During NRT

- quit

- Weight gain in lbs.

**p=<.05 in linear regression model, controlling for sex, treatment, and baseline BMI and cotinine**

***Lerman et al., ***_***Pharmacogenomics J***_***, 2004***

## Pharmacologic blockade of the mu opioid receptor is associated with reduction in nicotine reward in rodent and human models.

The low activity OPRM1 G allele is associated with a greater ability to quit smoking.

The mu opioid receptor and interacting proteins may be important targets for medication development, as well as for tailored treatment based on genotype.

**The low activity OPRM1 G allele is associated with a greater ability to quit smoking.**
**The mu opioid receptor and interacting proteins may be important targets for medication development, as well as for tailored treatment based on genotype.**

**Summary of Findings **

## Ultimate Objectives

**Identify novel targets for the ****development ****of nicotine dependence treatments**** **
**Improve the ****delivery**** of nicotine dependence treatment by targeting therapy to smokers based on biological profiles**
**Facilitate effective and ethical ****diffusion**** of new models of treatment delivery to the clinic and to the public**

## Acknowledgements!

***University of Pennsylvania: *****Wade Berrettini, Janet Audrain, Margaret Rukstalis, Paul Wileyto, Julie Blendy, Carrie Walters, Christopher Jepson**
***Georgetown University: *****Peter Shields, Alexandra Shields **
***University of Toronto: *****Rachel Tyndale, Sharon Miksys**
***University of Pittsburgh: *****Ken Perkins**
***UCSF:****** *****Neal Benowitz***** ***

*The following scientists contributed to the research findings in this presentation.....*

- This work was funded by a P50 TTURC grant from the National Cancer Institute