Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF₁ receptor antagonism

Abstract

Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Figure 1

Experimental timelines. (A) For heroin and cocaine self-administration studies, repeated paw withdrawal threshold (PWT) tests (indicated by arrows) were conducted before (baseline, BL) and during 1 h ShA training sessions. Subsequently, animals were divided into ShA and LgA groups, and PWT tests were conducted over this escalation phase. In a separate group of heroin self-administering animals, the effect of the CRF₁R antagonist MPZP on mechanosensitivity was determined post-escalation. (B) For the alcohol study, animals were tested before (baseline, BL) and after ethanol self-administration (0 weeks vapor exposure), and following 4 and 8 weeks of vapor exposure. Subsequently, the effect of CRF₁R antagonism on mechanosensitivity was determined over weeks 11–12 of vapor exposure.

Figure 2

Heroin self-administration and paw withdrawal thresholds in ShA and LgA animals. (A) Animals acquired heroin self-administration (n = 27) and upon transition to LgA conditions (12 h access, n = 15) significantly increased heroin intake. Asterisks indicate **p < 0.01 or *p < 0.05 significantly higher intake in LgA animals versus session one. (B) Paw withdrawal threshold (PWT) tests conducted during withdrawal revealed a development of mechanical hypersensitivity selectively in LgA animals following 7 and 15 sessions of extended access conditions (PWT tests 3 & 4, respectively). Pound sign indicates ^#p < 0.05 significantly lower PWTs in LgA vs. ShA animals (main effect of group). Asterisk indicates *p < 0.05 significantly lower PWTs in LgA animals versus baseline (BL) test. (C) Individual paw withdrawal thresholds at PWT 4 were significantly and negatively correlated with individual preferred levels of heroin intake during session 15 in LgA animals (r = −0.609, p = 0.016). (D) In another group of escalated LgA animals (n = 9) that displayed a significant reduction in paw withdrawal thresholds vs. ShA animals (n = 8), the CRF₁R antagonist MPZP significantly raised PWTs near levels measured in the ShA group, corresponding to a putative alleviation of heroin withdrawal-induced mechanical hypersensitivity. Pound signs indicate ^##p < 0.01 significantly lower PWTs in LgA vs. ShA animals (main effect of group). Asterisks indicate *p < 0.05 significant elevation of PWTs in LgA animals.

Figure 3

Cocaine self-administration and paw withdrawal thresholds in ShA and LgA animals. (A) Animals acquired cocaine self-administration (n = 18) and upon transition to LgA conditions (6 h access, n = 9) significantly increased cocaine intake. Asterisks indicate **p < 0.01 significantly higher intake in LgA animals versus session one (B) Paw withdrawal threshold (PWT) tests conducted during withdrawal did not significantly change over the course of cocaine self-administration under either ShA or LgA conditions.

Figure 4

Ethanol vapor exposure and paw withdrawal thresholds in ethanol-dependent and non-dependent animals. (A) Blood alcohol levels (BALs) of ethanol-dependent animals (n = 18) over the course of the experiment. (B) Paw withdrawal thresholds were not altered by ethanol self-administration (baseline test vs. 0-week vapor exposure test). Following eight weeks of ethanol vapor exposure, paw withdrawal thresholds in ethanol-dependent animals (n = 18) were significantly reduced compared to non-dependent animals (n = 18). Asterisk indicates *p < 0.05 significantly lower thresholds in ethanol-dependent vs. non-dependent animals at the eight week test. (C) During weeks 11–12 of ethanol vapor exposure, CRF₁R antagonism with MPZP significantly elevated the compromised paw withdrawal thresholds in ethanol-dependent animals (n = 12) near levels measured in the non-dependent group (n = 12), representing a partial alleviation of ethanol withdrawal-induced mechanical hypersensitivity. Pound signs indicate ^###p < 0.001 significantly lower paw withdrawal thresholds in ethanol-dependent vs. non-dependent animals (main effect of group). Asterisk indicates *p < 0.05 significant elevation of thresholds in ethanol-dependent animals.